Ovaries are an enigma that could unlock human lifespan
In the spring of 2017, celebrities and scientists gathered at the Los Angeles home of legendary television producer Norman Lear and his wife Lynn. The Hollywood power couple, outspoken supporters of myriad liberal causes, were also interested in the burgeoning field of longevity science. Among the speakers invited to update attendees on the latest advancements was Nicole Shanahan, the CEO of an intellectual property software company in Silicon Valley. Shanahan, a slight woman, with long, highlighted hair, told the audience about the relatively mundane but valuable process of tracking new research through the patent system.
She was followed on stage by Victor Dzau, a veteran doctor in his seventies and president of the US National Academy of Medicine. Dzau evangelised the importance of tackling ageing and announced a scientific competition seeking new ways to extend human lifespan. But Shanahan couldn’t concentrate. Her body grew hot and her face flushed, as her public role collided with her private hopes.
She and her partner, Google co-founder Sergey Brin, had been trying and failing to harvest eggs for a future conception. Despite being just 31, Shanahan was haunted by the fear that her life was being shaped by an organ that had been ageing since before she was born. Early in a female foetus’s development, she has about six million eggs. Only a couple of million make it to birth. By the time she hits puberty, she has 300,000 to 400,000 and then begins losing 1,000 immature eggs a month. By the time she’s 40, she may have fewer than 10 per cent left.
Shanahan flicked open the Flo app that tracked her fertility. “As I was watching another ovulation cycle go by, Victor was on stage saying, ‘We have to change the narrative on longevity. Ageing is a disease. It’s tractable. We have to treat this as a moonshot,’” she recalls. “And each one of those things went through my head as I was thinking about my own ovulation. It was a moment of powerful insight.”
At the cocktail hour after the presentations, Shanahan peppered every expert she could find with the same set of questions: “Have you heard about reproductive longevity? Who is working on this?” Shanahan had been closely watching Silicon Valley’s growing obsession with longevity. Between 2013 and 2022, funding for companies working in the field soared from $600mn to $4.6bn, according to PitchBook data. But she eventually found that, while men were funding myriad ways to lengthen their own lives, barely anyone was researching how to slow ageing ovaries and help women have children for longer.
When Shanahan scoured the patent corpus for advances on women’s reproductive longevity, she found “virtually nothing”. The only research was responding to the age-old pressure for women to look young. “It was mostly shiny hair and soft skin. It was very superficial, and none of it was about the core functions of being biologically woman,” she says.
In fact, science had neglected women’s health in general for decades, often seeing the differences in female bodies as confounding factors to be stripped out, rather than studied to improve the lives of more than half of the population. In the US, clinical trials were not obliged to include women until 1993. In the UK today, only about 2 per cent of medical research funding is spent on pregnancy, childbirth and fertility.
This lack of money for basic research means, from a scientific perspective, that ovaries — the glands which produce the eggs that guarantee the continuation of the human species — are essentially a mystery. Fundamental questions remain unanswered: why are the ovaries one of the first organs to age? Why does the quantity and quality of eggs fall so dramatically? Why do humans go through menopause when most animals do not? And why does the age of menopause vary wildly between individual women?
Shanahan has been on a quest for answers ever since. In the process, the 38-year-old became the most influential individual funder of reproductive longevity research. If she is successful, this new knowledge may have the kind of profound consequences that came with the arrival of the contraceptive pill. Advancements that could give women more control over their bodies and power a new era of equality. They could offer women more freedom to pursue careers and the right relationships, and help countries facing declining birth rates. And the ovaries, it turns out, could offer clues to extending the lifespan of all humans.
About a decade ago, Silicon Valley’s billionaires turned their attention to defeating death. They wanted to spend some of the proceeds of building world-changing technologies on clearing the final hurdle for humanity. A 2013 Time magazine cover breaking the news that the search company founded by Brin and Larry Page was funding a major new life-extension division, asked: “Can Google solve death?”
The idea seemed radical, even ridiculous, but there had been some recent breakthroughs to build on. In the previous two decades, researchers discovered more about genes and the metabolic pathways that dictate the pace of ageing and had even shown that extending lifespan was possible. At least, in worms and mice. Doing the same for human beings was merely another moonshot, like developing self-driving cars or landing on Mars.
But, in practice, Silicon Valley’s “move fast” ethos sometimes collided with the glacial pace of medical development. Some entrepreneurs experimented on themselves, engaging in so-called biohacking. When experiments showed that blood transfusions from younger to older mice could rejuvenate their brains, some biohackers began to seek young plasma. The practice was skewered on HBO’s Silicon Valley in the form of ghoulish tech billionaire Gavin Belson conducting pitch meetings with his “blood boy” in tow. Other techies obtained off-label prescriptions for drugs such as metformin, the diabetes medicine that researchers hypothesise could slow ageing, but have not yet definitively proven.
Then there were the extreme personal regimes. Ray Kurzweil, the famed inventor and a Google executive, consumed a daily diet of a hundred pills, as part of a plan to be frozen after death and resurrected by future technology. More recently, the entrepreneur Bryan Johnson, who has spent millions on trying to reverse his body’s ageing, has become a reliable generator of bizarre headlines. (He stopped infusing blood from his 17-year old son, though, deeming it ineffective.)
Shanahan had a front-row seat as Brin launched Calico, Google’s ambitious life-extension moonshot. She was generally critical of the “longevity bros”, the cadre of men in Silicon Valley who cannot accept their impotence in the face of death. “The primary male-tech-founder attraction to longevity comes from a fear of death. A real fear of death, the afterlife, spirituality and justice,” Shanahan says. “My experience with these individuals is that it is very much self-motivated.”
Shanahan grew up in a Bay Area, far removed from Silicon Valley’s power elite. Until she was 17, she lived in Oakland. Her family was on government assistance, and Shanahan craved a “very stable middle-class American life, with a dad and a mom and children and a dog”. She went to university at Puget Sound in Washington State, later becoming a lawyer and an entrepreneur. She met Brin in 2014 at a yoga festival in Tahoe, California; they were married four years later.
A craze for egg-freezing had swept through Silicon Valley before the couple started trying to get pregnant. Large tech companies such as Apple and Facebook added costly oocyte cryopreservation — freezing a woman’s younger, healthier eggs in order to postpone pregnancy — to the long list of employee benefits, alongside free meals and laundry. At the time, Shanahan believed that “was the ultimate new tool for extending female reproductive years”. But she quickly discovered it was not a simple process, repeatedly going to clinics to find that she couldn’t have the procedure that month because of cysts on her ovaries. She recalls being offered little information or advice beyond to try again the following month. “This was very disruptive to my life,” she says. “I was a CEO of a start-up. I was beginning my philanthropic career. And I was running a household with Sergey, who was still very active at Google, and I had stepkids.”
By the fifth time she was turned away, she was emotionally exhausted and exasperated with a system that seemed at best a “Band-Aid”. “You begin to question your entire existence,” she says, pausing to remember how she felt at the time. “You begin to think of what a life is like [if you] never have children. And that is painful. It’s scary. It’s saying goodbye to something before you even had a chance at it.”
Shanahan felt IVF was sold as a “saving grace” to her and her peers. The statistics show that is far from the case. Each round only works about one-third of the time for a woman under 35, with success rates falling as she ages. Shanahan began to view IVF as a “commercial endeavour” rather than a scientific one. “It became abundantly clear that we just don’t have enough science for the things we are telling and selling to women,” she says. She admits her opinion is unpopular, then adds: “It’s one of the biggest lies that’s being told about women’s health today.”
The curved white stone building that houses the Buck Institute for Research on Aging rises above the mist on a hill in Marin, over the bay from San Francisco. Inside, experts in white coats study worms, mice and humans to discover more about the basic mechanisms of ageing and age-related diseases, such as neurodegeneration and cancer. The Buck began its pioneering work in the late 1990s, after oil heiress Beryl Hamilton Buck donated part of her estate to help the aged of the county.
In late 2017, Shanahan drove up the winding road to the summit where the institute is located. She was planning to pitch her software, but her mind was still whirring from the event at the Lears’. Shanahan remembers being the only woman in the meeting. “On a whim,” she decided to pitch research on reproductive ageing. Though she was essentially offering to fund the work, her suggestion was met by a “respectful ambivalence” in the room.
But when the idea was floated internally, it generated considerable excitement, particularly from the women. The biggest cheerleader was Jennifer Garrison, a fast-talking neuroscientist in her forties, who started her career at Nasa. When they first met, Garrison was surprised by Shanahan’s youth and her casual demeanour. Shanahan was somewhat suspicious that Garrison was a neuroscientist, with no history of working on women’s reproductive health. “I was like, ‘Well, this is a big jump isn’t it?’ And she said, ‘No, I think reproduction starts in the brain,’” Shanahan recalls. (Garrison is interested in how the brain’s control centre, the hypothalamus, sends signals about ageing around the body, including to the ovaries.) “And I was like, ‘Well, who am I to say otherwise? Let’s do it.’”
The result was the Center for Reproductive Longevity and Equality and a consortium that makes philanthropic investments in reproductive longevity research. Garrison is the centre’s director, helping decide where bets are placed. Scientists at the Buck began to work on reproductive ageing projects, looking at how a key coenzyme that influences metabolism, by helping enzymes, can affect ovarian reserve and reproductive lifespan, and studying how the conversation between the brain and the ovaries changes as we age.
Shanahan wasn’t simply funding a field but creating one, pulling together expertise from across the sciences. Just three of the original 23 grantees had any background in the area. To help scientists enter the field, the centre plans to run “ovary bootcamps”, where researchers can learn to experiment on animal ovaries, as well as a biobank for human tissue, which is hard to obtain because few women donate their ovaries to research. Garrison draws a clear link between the lack of funding and the lack of knowledge about how women’s reproductive systems age. “There’s not enough data for doctors to treat their patients,” she says. “There’s not enough data for us to understand literally how the female body works, so that we can think about menus of treatments . . . rather than Band-Aids.”
Garrison is not inspired by a sci-fi vision of elderly women having babies, a generation of female Mick Jaggers. She says she doesn’t have a “strong opinion” on whether women should have children at 70, but that’s not the aim of the work. The aim is to slow down the process and improve the symptoms of the menopause. “The fact that we go through menopause right in the middle of our lives really has a strong effect on everything we do as adults. Every choice we make has to be somehow informed by that knowledge,” she says. Moreover, it affects health in almost every way, from cognitive function to bone strength. “Going through menopause is the worst thing that can happen to a woman in terms of her health,” Garrison says. “It’s not like a gradual decline. It’s like falling off a cliff.”
In 2018, Shanahan got pregnant “magically”, without intervention, and gave birth to a daughter. It was a happy turn of events that she says highlighted how little the fertility clinics had really known about her body. “I’m learning now that it wasn’t magic at all. I was actually very healthy. And it turns out many women have these moments of surprise conception when they least expect it.”
By then, Shanahan was well on her way to widely funding reproductive longevity research. In 2019, she travelled to Washington, DC, to announce a $10mn donation at the National Academy of Medicine. Before she went on stage, she discussed the plan with the men at her table, directors of health agencies from around the world. “I gave them my pitch on women’s reproductive longevity as a field of science,” she recalls. “And I thought that I was making such incredible headway because everyone was nodding. I was like, this is fantastic. They really understand. And then once I finished my pitch, the first question asked was: ‘Well, what about sperm?’”
When her name was called, Shanahan headed to the stage, feeling outraged that supposed leaders in the field couldn’t manage to focus on the need to fund women’s health. So she upped the ante, surprising many in attendance by announcing a far-larger commitment of $100mn.
The money should help scientists fill the gaps in our understanding of women’s health. One place to start is by investigating why human women are so different from many female animals. The consortium is funding researchers who study ants. Some species can oscillate between fertile and infertile periods; some have fertile queens that can live for up to 30 years. Other scientists backed by Shanahan are examining naked mole rats, which make eggs as adults and have exceptionally large ovarian reserves that help keep them fertile their entire lives.
Deena Emera, an evolutionary geneticist affiliated with the Buck and the author of A Brief History of the Female Body, says the animal kingdom could hold the key to problems humans are trying to solve. She is fascinated by the bowhead whale, a species that reproduces until it is 100 years old, at least. “At some point, their ancestors didn’t live as long,” says Emera, “and their maximum lifespan got longer. My hypothesis is that their reproductive lifespan also got longer. That was something that evolved.”
Emera is using her grant to compare the genomes of these giant mammals with other species, hoping to identify telling differences. If she can obtain whale ovaries, she wants to examine how the genes are expressed in the tissue. “If there are really high levels in the bowhead whale ovary, what is that gene? And is it expressed in high levels in the human ovary or in the beluga whale ovary, which experiences menopause?” she asks. Emera’s work is in the very early stages. But if she does land on a key gene, she could attempt to manipulate it in mice and create a model for further experiments. Eventually, that could guide scientists to develop treatments that make humans a little more like those forever-fertile whales.
In 2019, Shanahan started discussions with the National University of Singapore about creating another research centre. Zhongwei Huang, an obstetrician and professor at the university, was already lobbying for more funding. “I tell the women in front of me, ‘I’m sorry, you are so-and-so old. And, unfortunately, your egg quality is so bad because of your age,’” he says. He felt he was being disingenuous since some women are able to have children at older ages than others. “I realised, ‘Oh my god, this is the research that I should be doing: to find reasons why is this woman different from that woman.’”
Huang is collaborating with fertility centres to discover more biological signs that indicate ovarian conditions, so that doctors get better at predicting women’s individual reproductive lifespans. Like some other researchers, Huang is intrigued by the potential of existing commercial drugs to extend overall lifespan. One example is rapamycin, originally developed as an immunosuppressant for organ transplant patients. It is now tested as a potential anti-ageing drug because it targets the mTor pathway, which regulates cellular growth and longevity. Scientists at Columbia University, who had their initial work funded by Shanahan’s consortium, are now running a larger trial looking at whether rapamycin could delay the start of the menopause.
Francesca Duncan, who runs labs at Northwestern University and the Buck, was one of the few scientists working on reproductive ageing before Shanahan arrived. She says she was seen as an “oddball” in the longevity field, with many peers refusing to see what happened to women in their thirties as “ageing”. When Duncan was at the University of Kansas, technicians in her lab noticed that the older the ovary, the harder it was to physically extract the eggs. Down the hall in the toxicology department, researchers were studying liver fibrosis, when the tissue becomes rigid with age. Duncan realised ovaries were suffering from the same problem.
Now, she is working to develop ways to measure this stiffness to track ovarian ageing using ultrasound techniques. “I really liked this concept of explaining the nest, or the environment of the egg,” Duncan says. “Because if you can fix that nest, that’s going to help that egg stay there for longer and be better quality.”
The consortium is not currently funding work on one area that has given some scientists’ hope: in vitro gametogenesis. Researchers are experimenting with using stem cells to create new eggs and sperm from any cell in the human body. So far, this has only been achieved in mice, but advocates hope it could solve fertility problems in people and even enable same-sex couples to have children who combine their genes. Such an advance would have enormous commercial potential. Garrison says this would be “very challenging” to replicate in humans and doesn’t believe it will ever be possible.
If successful, extending the age at which women can have children significantly would raise big questions. Would it end the “motherhood penalty” on women’s salaries and career progression? What would the impact of having older mothers (and fathers) be on children? And, does it risk being a societal sticking plaster, where a drug is used to change women’s biology, instead of reforming the worlds of work, childcare and relationships to suit women’s needs?
Giacomo Vagni, a sociologist at the University of Essex who studies gender inequality, says there is evidence that women who have children later in life do not have as large a hit to their potential earnings, because they are more established in their careers. “If a woman could have kids in her fifties, I think the penalty would definitely be much smaller,” he says, adding that it also might stop companies from stigmatising women in their thirties who are viewed by some employers as more likely to take maternity leave.
Bioethicists are divided on how to think about the welfare of offspring born to older mothers, who will probably lose their parents earlier in their lifetimes, according to Glenn Cohen, a professor at Harvard Law School. “Some say given the alternative is that no child exists, losing a parent early is not good but it is better than not existing at all,” he explains. Others are inclined to prioritise what is “species typical”: treating a woman whose fertility lags behind the average, rather than extending it beyond the norm, he adds.
In theory, medical progress should not prevent policies to achieve broader gender-equality goals. But it can be easier to sell a drug than to shift society. Just as the new generation of obesity medicines risks letting governments off the hook for ensuring universal access to healthy food, a breakthrough in female reproductive longevity could make it easier to ignore the challenges to earlier parenthood.
Shanahan recently rewatched a video of the first time she mentioned that longevity science could be important for women’s equality. She was still giving presentations about patents but, this time, she noted it was her “deeply held belief” that progress in longevity research would track with social progress. “We live in a time where most of us believe that we are created equal,” she said, being interrupted by audience laughter at the clipart of gender symbols balancing on a see-saw on the screen above her. “But in reality, half of us, meaning half of humankind, lose access to a fundamental part of themselves at the age of 30.”
Looking back, she says her early attempt to make this connection was “awkward and I didn’t get it all right, but it was a first step”. She explains that she felt at the time that framing women’s health as part of longevity medicine was the “richest opportunity” to progress the women’s movement. Seven years later, as more and more funds invest in longevity companies, she still faces a “deafening silence” when she asks if they would be interested in funding reproductive longevity research.
Unlike many of her male peers, Shanahan did not jump to start a company to tackle the problem, distrusting the commercial interests that were fiddling with women’s fertility. Speaking at a National Academy of Medicine event last year, she explained that she’s unusual in not having a commercial motive and then added, laughing: “I got a divorce so I have less conflicts now. So yay for me.” (She and Brin separated in 2022.)
Instead, she is funding academic scientists who are working on the most fundamental problems. Because she is not seeking profit, she can also fund clinical trials for interventions that do not make money, such as whether exposure to sunlight could impact reproductive health. “The world of funders is really divided into those with commercial interests and those without, and it’s a lonely space in the field of medical science for those who have no commercial interest,” she says.
Her work raising the profile of the problem has drawn in more government funding — from Singapore and the US National Institutes on Aging — but it is nowhere near enough. To create drugs that could really change women’s (and men’s) lives, scientists will need more than Shanahan’s $100mn. She believes a “nice lofty goal” would be to raise $500mn, which would have a “massive impact on the field”. Shanahan hasn’t given up on recruiting men to the cause, urging them to see that this longevity problem is shaping billions of women’s lives right now, as well as possibly helping with their ambitious plans to extend lives like their own.
There are even questions that longevity bros might want answered. One population study showed men whose sisters who had children after 45 were likely to live longer. One hypothesis is women who go through menopause later are better at repairing damage to their DNA — and their brothers also have this trait. Finding out whether the ovaries offer clues about extending all human lifespan will require more funding, more research. But “a lot of the male philanthropic funders might feel that it’s out of their league,” Shanahan says. “I’ve heard one man tell me, ‘That’s above my paygrade.’ I would love to put the message out that they have everything they need to know, they are fully qualified to fund this space, and we would welcome it.”
Hannah Kuchler is the FT’s global pharmaceutical editor
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