Seeing gray hairs or wrinkles in the corners of the eyes are tell-tale signs of getting older. But for women, aging starts far deeper than the skin’s surface. Female reproductive organs begin aging precipitously when women are in their 30s — decades before most other organs begin to decline. The number and quality of eggs in the ovary dwindles; hormones such as estrogen and progesterone become scarce; and menstruation grinds to a halt.

This precocious aging is still poorly understood, in part due to underinvestment in women’s health research, but also because of the longstanding view that the ovaries and uterus only play a role in women’s fertility. Early studies of female reproductive aging largely focused on the fact that most women are no longer able to become pregnant by the time they turn 55.

These organs actually influence far beyond reproduction. “By calling them reproductive organs, we’re essentially pigeonholing all of women's health through the lens of fertility and reproduction,” said Jennifer Garrison, an aging researcher at the Buck Institute for Research on Aging and director of the Global Consortium for Reproductive Longevity and Equality. 

Cells in the ovaries communicate with almost every organ in the body, and as a result, they can influence the function of everything from the liver to the brain. Researchers have linked hormones released by the ovaries to memory, heart health, and bone strength. When aging ovaries stop making these hormones, it can wreak havoc. Because this happens earlier than other aspects of aging, women suffer the consequences for decades.

“Women are living about half their lives in this suboptimal hormone environment,” said Michele Pritchard, a researcher studying inflammation at the University of Kansas Medical Center. 

Reproductive aging can be a “pacemaker” of sorts that sets the tempo for the whole body’s aging. Emerging research that cuts across disciplines reveals what many women have long known: female reproductive aging has consequences for women’s health more broadly (1). That means that improving women’s health across their lifespans requires a better understanding of how reproductive organs age. To bring this about, researchers track how ovarian physiology changes with age, measure signatures of reproductive aging, and trace down the source of the signals that spur ovaries to age with hopes of informing technologies that empower women to control their own reproductive aging. 

Building a better nest

Although the link between the reproductive system and whole-body aging has only recently become mainstream, there have been clues scattered throughout decades of developmental and epidemiological research. In 1999, researchers at the University of California, San Francisco noticed that when they used lasers to destroy the key cells required to make eggs and sperm, nematode worms lived longer (2). The absence of these cells seemed to alter insulin signaling and slow down aging processes. Errors in the production of eggs lead to accelerated aging in worms (3). In large human cohorts, researchers noticed that earlier age at puberty or menopause correlates with higher risk of chronic diseases such as diabetes and cardiovascular disease (4,5).

By calling them reproductive organs, we’re essentially pigeonholing all of women's health through the lens of fertility and reproduction. 
– Jennifer Garrison, Buck Institute for Research on Aging

Menopause itself has puzzled aging researchers. While many species undergo a decline in fertility as they age, the specifics of the process vary across species (6). Greenland sharks, for example, only start reproducing at the ripe old age of 150. Some aphids are born essentially pregnant with the next generation. Nonetheless, “All organisms seem to be governed by fundamental trade-offs between early and late life reproduction,” said Mike Garratt, an aging researcher at the University of Otago. 

Comparative studies of menopause have been challenging because the traditional definition in humans — 12 months since last menstruation — doesn’t translate to other species. However, at least some other species such as cows and orcas seem to also stop ovulating and reproducing relatively early in the female lifespan (7).

For Francesca Duncan, a reproductive scientist at Northwestern University’s Feinberg School of Medicine, one of the most intriguing aspects of menopause is just how consistent the core elements of the process are across women. “It's a very robust phenomenon,” she said. “Every single woman is going to experience it.” 

She began studying reproductive aging with a focus on the eggs. Women are born with all their eggs stored in their ovaries, and in each menstrual cycle, one egg bursts forth from a follicle to journey through the fallopian tube to the uterus. Over time, the eggs in the ovary may die, fail to be released properly, or develop genetic abnormalities.

Duncan soon realized that eggs were only one part of the story. As she and her students tried to extract eggs from mouse ovaries, they noticed that the older the mouse, the harder it was to squeeze out the eggs. The ovaries seemed stiffer, akin to organs that have undergone scarring.

Duncan turned to Pritchard, who studied how inflammation leads to fibrosis and whose lab was in the same building. By repurposing the tools that Pritchard used to study the scarred livers of people with chronic alcohol use, the duo discovered that as the ovaries age, they are infiltrated by inflammatory immune cells and develop layers of stiff, fibrotic scar tissue (8). 

They hypothesized that the scars may trace back to follicles bursting open each month to release eggs. Each time this happens, it creates a wound that needs to heal. “There's a lot of cell death that happens in a normal, healthy ovary that has to be dealt with,” Duncan said. “As you get older, the ability of that organ to clear that damage becomes less effective.” 

In subsequent studies, Duncan and Pritchard analyzed the mechanical properties and molecules of the ovary (9). They pinpointed hyaluronan as a key protein that maintained normal follicular structure, but found that during aging, hyaluronan broke down and was replaced by collagen. 

They think that this points to a new way for therapies to improve ovarian function and counteract the damage wrought by aging: creating a better “nest” for the eggs, as Duncan described it. Studies in mice have already shown that removing fibrotic collagen from the ovaries extends reproductive lifespan (10). Pritchard is interested in finding a way to use hyaluronan to recreate an ovarian environment conducive to the development of healthy follicles that can house eggs and release hormones. “More attention has to be paid to the mechanics of the organ,” she said.

A balancing act

The effects of ovarian stiffness may also be seen far away from the eggs in their “nest,” in part because the ovaries produce and respond to a large complement of signaling molecules. Many of these molecules interact with the brain. “At some level, the brain ultimately controls all aspects of female reproduction,” Garrison said. “It's not really like a dictator, though. It's constantly listening to and integrating feedback.”

One region of the brain that seems especially relevant is the hypothalamus, a control center that sits deep within the brain and regulates homeostasis throughout the body. It forms part of the hypothalamus-pituitary-gonadal (HPG) axis, which controls reproduction by sending signals through neurons or through chemicals released into the bloodstream. The hypothalamus’s mission is to maintain balance, and at times, this requires shutting down the reproductive system because there are more pressing needs, for example, to fight an infection or to conserve energy in a famine. 

“[Reproduction] is costly for an animal in the wild,” Garratt explained. “It requires a lot of energy.” Kisspeptin neurons in the hypothalamus are responsible for integrating these signals from the body’s various systems to decide whether the time is right for reproduction. In a sense, they are the “gatekeepers of fertility,” Garratt said.

Molecular signals within cells also play a role in budgeting energy resources to determine when to reproduce. Arjumand Ghazi, a developmental biologist at the University of Pittsburgh School of Medicine, found that the nematode TCER-1 elongation and splicing factor regulated whether worms expressed genes that promote reproduction or genes that promote longevity, such as immunity or stress resistance genes (11,12). Under normal conditions, high levels of the protein promoted reproduction. But if TCER-1 levels remained high under dangerous conditions, such as during an infection, this became a liability for the worms. “If things became bad, then having lots of this protein told the animal, ‘Things are fine, continue to reproduce,’” she said. “That took away resources from the ability to fight off pathogens.”

In subsequent unpublished work, Ghazi found that TCERG1, the human homolog of TCER-1, is highly expressed in human egg cells, and that the levels go down with age as women reach menopause. Her lab also found that genes involved in fat metabolism are involved in reproductive regulation, which is unsurprising, she said, given the energy demands of reproduction.

The way that energy balance influences reproduction can also have unexpected consequences. For example, dietary restriction shuts down the HPG signaling required for reproductive functions. This starts in puberty and seems to involve leptin, a hormone that maintains energy balance. However, in mice, pausing reproduction allows the animal to keep its ovarian egg reserves intact. Without losing eggs to follicle destruction or menstruation, their fertility extends to older ages when food becomes available again (13).

This doesn’t mean that eating less is the key to extending reproductive years. Dietary restriction can be dangerous, and it affects the body in numerous ways, including by signaling to the brain and changing hormone levels. Researchers don’t know which of these consequences maintain the ovarian health in mice. To disentangle the neurological and metabolic mechanisms, Garratt and his collaborators are inactivating the main hypothalamic neurons that normally respond to dietary restriction by turning reproduction on or off. Then they will measure whether dietary restriction still influences reproduction through other metabolic pathways. Garratt hopes that this will inform ways to keep follicles intact for longer, although he noted that translating this to humans is still far away. 

Treating the body through the ovaries

Duncan has studied reproductive aging throughout her career, but she has noticed an “explosion of interest” in the past five years. Women increasingly choose to delay childbearing to later in life through birth control, freezing their eggs, and other reproductive technologies. Since 1970, women’s average age at childbirth in the United States increased from 21 to 27 (14,15). The projected continuation of this trend has spurred widespread innovation, such as the development of artificial uteruses and ovaries, or ways to freeze ovarian tissue and transplant it back into the ovaries after their function has diminished (16). Understanding ovaries and how they age will help make these technologies better, Pritchard said.

Aging research also points to potential therapeutic targets for ovarian diseases, such as ovarian cancer and polycystic ovarian syndrome. For example, Duncan noted, ovarian cancer latches more tightly to collagen-rich tissue, such as the scars found in older ovaries. She thinks that antifibrotic drugs could help make the environment less hospitable for the tumors. “Targeting the environment is going to be critical because, to me, it's one of the only ways that we can get at the root of the problem,” she said.

Researchers noted another equally stark change over the last century: medical advances have extended the human lifespan by nearly a decade, which means that women are living longer past menopause. That means that they are more likely to suffer from aging-related diseases such as osteoporosis, for which the risk dramatically increases after menopause due to the decline in estrogen. Duncan hopes that reproductive innovations that focus on the ovaries will benefit women throughout their lifespans. “If you can modulate the [ovarian] environment, you can not only extend fertility but also the overall endocrine function of that organ,” she said.

Ghazi noted that improving women’s health after menopause might require looking beyond fertility. She thinks about this challenge as two-pronged. On one hand, there’s the question of extending fertility. She envisions using what she and others have learned about the factors that damage and destroy ovarian follicles to develop a pill that prevents the loss of follicles when women enter their 30s.

On the other hand, there’s the question of extending women’s “healthspan,” or the portion of life in which they are healthy. She and others think that understanding the molecules involved in reproductive aging could inform diagnostics that give individualized advice on staying healthy. “The goal really is to understand how to preserve [ovaries’] health-promoting function,” Garrison said.

I hope we will be able to change the narrative. The reproductive system in women is not only relevant for their fertility. It has far-reaching consequences for every aspect of their lives. 
- Arjumand Ghazi, University of Pittsburgh School of Medicine

Ghazi is currently conducting a study to identify RNA biomarkers of accelerated aging in blood and saliva of women with reproductive diseases such as Turner Syndrome. In this condition, women are missing one X chromosome and are often unable to go through puberty or become pregnant without fertility treatments. While this is a relatively extreme form of reproductive decline, she thinks that these markers could construct a useful barometer for detecting the whole-body influence of reproductive aging in many women.

Garrison envisions that biomarkers like this could one day have a place in the clinic. “What will happen ideally is that we'll have enough of an understanding of how things change that we can take an individual who's 28, understand what her genetic and environmental risk factors are, and then say, ‘These are the pathways that we can modify now that will preserve her ovarian function in synchrony with the rest of her body,’” she said.

The idea of calibrating ovarian function as a way to maintain overall health may currently feel extreme, but evidence is building to suggest that these tiny organs have an outsized influence on health. “I hope we will be able to change the narrative,” Ghazi  said. “The reproductive system in women is not only relevant for their fertility. It has far-reaching consequences for every aspect of their lives.”

References

1. Gilmer, G. et al. Female aging: when translational models don’t translate. Nat Aging  3, 1500-1508 (2023).
2. Hsin, H. & Kenyon C. Signals from the reproductive system regulate the lifespan of C. elegans. Nature  399, 362-6 (1999).
3. Loose, J. A. et al. Meiotic dysfunction accelerates somatic aging in Caenorhabditis elegans. Aging Cell  21, e13716 (2022).
4. Day, F. R. et al. Puberty timing associated with diabetes, cardiovascular disease and also diverse health outcomes in men and women: the UK Biobank study. Sci Rep  5, 11208 (2015).
5. Hu, F. B. et al. Age at natural menopause and risk of cardiovascular disease. Arch Intern Med  159, 1061-6 (1999).
6. Jones, O. R. et al. Diversity of ageing across the tree of life. Nature  505, 169-73 (2014).
7. Winkler, I. & Goncalves, A. Do mammals have menopause?Cell  186, 4729-4733 (2023).
8. Briley, S. M. et al. Reproductive age-associated fibrosis in the stroma of the mammalian ovary. Reproduction  152, 245-260 (2016).
9. Amargant, F. et al. Ovarian stiffness increases with age in the mammalian ovary and depends on collagen and hyaluronan matrices. Aging Cell  19, e13259 (2020).
10. Umehara, T. et al. Female reproductive life span is extended by targeted removal of fibrotic collagen from the mouse ovary. Sci Adv  8, eabn4564 (2022).
11. Amrit, F. R. G. et al. DAF-16 and TCER-1 Facilitate Adaptation to Germline Loss by Restoring Lipid Homeostasis and Repressing Reproductive Physiology in C. elegans. PLoS Genet  12, e1005788 (2016).
12. Amrit, F. R. G. et al. The longevity-promoting factor, TCER-1, widely represses stress resistance and innate immunity. Nat Commun  10, 3042 (2019).
13. Selesniemi, K. et al. Moderate caloric restriction initiated in rodents during adulthood sustains function of the female reproductive axis into advanced chronological age. Aging Cell  7, 622-9 (2008).
14. National Center for Health Statistics. American Women Are Waiting to Begin Families: Average Age at First Birth up More Than 3 Years From 1970 to 2000. Centers for Disease Control and Prevention (2002).
15. Schaeffer K and Aragão C. Key facts about moms in the U.S. Pew Research Center (2023).
16. Johnson, J. et al. Modeling delay of age at natural menopause with planned tissue cryopreservation and autologous transplantation. Am J Obstet Gynecol  430, 426.e1-426.e8 (2024).