Women Are Having Kids Later. Longevity Scientists to the Rescue?

By Kristen French

Illustrations by Mikyung Lee

Narwahls and beluga whales share something surprising with humans that few other species do: menopause, an abrupt end of reproductive capacity long before the end of life. Humans are pretty much the only primates who undergo menopause, which typically starts in a woman’s late 40s to early 50s. Most monkeys don’t. Mice don’t either. Mice can have babies right up until the very ends of their lives. While some evolutionary explanations have been proposed, including the “grandmother hypothesis,” which posits that the extra care infertile grandmothers can provide makes for stronger grandkids, we still don’t really know why humans — and some whales — are different from other mammals in this respect.

In fact, female reproductive aging, the aging of the ovary, remains largely a mystery to science. It is a particularly glaring knowledge gap given the recent boom in aging research.

But help may be on the way. Last July, the Buck Institute for Research on Aging, one of the world’s leading institutions on aging research, announced that it is establishing a Center for Female Reproductive Longevity and Equality with a $6 million gift from Nicole Shanahan, an attorney, tech entrepreneur and research fellow at Stanford’s CodeX. (She is also the partner of Google founder Sergey Brin, one of a handful of Silicon Valley billionaires who has invested heavily in life extension and longevity research.)

Shanahan’s grant was the impetus for the launch of the center. She became personally interested in the subject of reproductive aging as she struggled with her own fertility in her early 30s, and noticed that it was a neglected subject in the field of aging research. During an unrelated work visit to the Buck, she floated the idea of such a center to CEO Eric Verdin and was met with enthusiasm.

The launch is timely for many reasons: It has been well documented that women are increasingly delaying having children, for career and other reasons, though childbirth after 35 is linked to increasing risk of complications, miscarriages, and birth defects. But medical interventions and better preventative healthcare are also extending women’s lives post menopause, increasing the number of years they must contend with an altered hormonal environment that is hard on their cardiovascular health, immune system health, and bones.

Growth in the field of aging research more broadly means substantial groundwork has been laid for the study of reproductive aging — small investigational studies suggest that the molecular mechanisms underlying aging in ovarian and other tissues are the same: faulty DNA repair, metabolic and energetic disorders, mitochondrial dysfunction, inflammation and protein dysfunction. So breakthroughs in our understanding of reproductive aging may illuminate the broader processes at work in aging more generally.

The new center’s launch happens to coincide with an opening of interest in the subject of reproductive aging from the National Institute of Aging (NIA), the primary federal agency supporting and conducting Alzheimer’s research. Early this year, the NIA announced plans to make the basic biology of aging in reproductive tissues a funding priority for the first time. Until now, most federal funding for research on fertility and infertility came from the National Institute for Child Health and Human Development.

Francesca Duncan, Ph.D., an expert in the field of reproductive aging at Northwestern University in Chicago, is encouraged that reproductive and aging science communities will begin working together. “It’s almost like you have two different disciplines,” she said. “We really need those two communities to come together to tackle this problem.” The Buck Institute’s new center represents a shift in this direction, she added.

“I don’t think the goal is to have 80-year-old women having babies,” cautioned Judith Campisi, Ph.D., a professor of biogerontology at the Buck Institute. But to extend the productive years for women in their 30s and 40s? Hopefully, yes. About 10 percent of women are infertile by the time they turn 35, and at age 40, a woman has only about a 5 percent chance of becoming pregnant in any month. For this reason, pregnancies in women over the age of 35 are often referred to as “geriatric” pregnancies.

As women delay childbirth, “how can we keep their reproductive systems vibrant so that when they are ready to have children they don’t have issues?” asked Campisi — a question the Center for Female Reproductive Longevity and Equality is seeking to unravel. Campisi, whose lab at the Buck Institute studies the connections between cellular senescence and age-related conditions, is a member of the recruiting committee for the new center.

Finding ways to protect against declines in healthspan associated with onset of menopause is as or perhaps even more important to the Buck team. Early menopause is associated with higher mortality risk in women, and possibly dementia. Women who naturally go through menopause before age 40 are twice as likely to die at any given moment compared with women who get natural menopause between the ages of 50 and 54. This clearly has a genetic component: Brothers of women who go through menopause later also tend to have longer lifespans. Later menopause is also linked to lowered risk for and delayed onset of some age-related diseases, such as osteoporosis, heart disease, and diabetes.

But the first priority of the Buck’s new center will be to settle big questions about the basic science behind female reproductive aging. Why do human females go through menopause? Why is the onset of menopause linked to negative health effects in women? And why is the timing of menopause so highly variable within the lifespan, from one individual to the next? The answers to these questions could, within a couple of decades, help the researchers design interventions to delay ovarian aging, treat early onset menopause, and extend endocrine, or hormone, function to improve organ system functioning and healthspan, said Jennifer Garrison, Ph.D., a neuroscientist at the Buck Institute, who is leading the effort to recruit faculty and researchers for the new center.

While many components, processes, and tissues are involved in female reproductive aging, ovarian aging will be the primary focus of the research center, at least at the start. Beyond that, the direction will be significantly shaped by the scientists the center hires to lead it, said Campisi, a process they hope to complete by June. That direction will also be driven, of course, by collaboration with other experts in the Buck’s 19 labs, including those who work on stem cells and regenerative medicine, cellular stress and disease, mitochondria and bioenergentics, and nutrition and metabolism. “One of the strengths of the Buck is that we all end up collaborating one way or the other,” said Campisi. “And so this would add a new dimension.”

For now, Campisi and others at the Buck are getting a crash course in reproductive aging, with experts in the field coming in to give talks and lectures. One such expert, for example, was Allen Spradling, Ph.D., who runs the Carnegie Institute outside of Baltimore, and who has been studying reproductive aging for many years, primarily in drosophila, a genus of fruit flies, but also in mice. “We’re all kind of at the graduate student level today,” said Campisi. “None of us are true experts.” At least, not yet.

Perhaps the most fascinating mystery of female reproductive aging is the most basic one: Why does menopause hit women so young? Human aging is generally a coordinated process, managed by the brain. A person’s heart, for instance, typically declines at about the same rate as her liver. Menopause is out of synch, happening typically in the 50s and sometimes the late 40s, decades prior to advanced aging in the rest of the body. In fact, when human females begin to experience a loss of reproductive capacity, in their 30s, the rest of their somatic tissues are reaching peak performance.

Some tentative answers are beginning to emerge. Scientists have known for some time that a woman’s chances of pregnancy declined in her 30s, regardless of race or ethnicity, due to a decline in the quantity and quality of the eggs produced by her ovaries. Declines in quantity made some sense — women are born with a fixed quantity and the eggs, once released, are gone — unless they are retrieved for fertility treatment. But why those eggs declined in quality in an otherwise healthy individual was not clear. More recently, Francesca Duncan’s lab at Northwestern discovered that older ovaries harbor large tangles of fibrous tissue caused by inflammation, which may interfere with their ability to nurture healthy eggs.

Now Duncan and her team are trying to understand whether they can mitigate the fibrosis and inflammation to improve outcomes as the egg develops. Her lab has partnerships with a group at Northwestern, under neurologist Jeff Savas, Ph.D., that studies neurodegenerative conditions such as Parkinson’s and Alzheimer’s, which are associated with the accumulation of tangles of long-lived proteins that don’t regenerate. Together, they are asking: Do we see a similar phenomenon in the ovary, given that a woman starts life with all of her eggs, or oocytes, and that these have to sit around in perfect condition for up to 50 years?

“There’s a lot of work that’s being done on cancer, showing that the environment in which a cancer cell finds itself can dictate so much about that cancer, like how aggressive it is,” said Duncan. But when it comes to the aging of an egg, “we really never really thought about that. Where is that [egg] going to be growing and is that environment permissive to the growth of a high quality egg?” Instead, most egg biologists have tended to extract the egg from the ovary and look at it in isolation.

If you look at a cross section of an ovary, you’ll see eggs that are at different stages of development, said Duncan. The smallest eggs in that cross section represent the ovarian reserve, the primordial follicles, and they really dictate the reproductive lifespan of an individual. These follicles are thought to be quiescent until they are activated to grow in waves. But there is a lot of other stuff inside the ovary, as well: vascular cells, smooth muscle cells, various different kinds of immune cells that change during the cycle, fibroblasts, and a complex web of proteins and other components called the extracellular matrix, which provides a scaffold for all of this other cellular material.

We’re finally understanding that there are multiple organelles and components of the cell that are contributing to this aging process in the egg, said Duncan. And even beyond the egg itself, that the environment of the ovary contributes, and then beyond the environment of the ovary, the whole body of the individual. A whole host of external factors can accelerate that biological clock.

It is unlikely, said Duncan, that we will be able to single out one therapeutic strategy that’s going to fix every part of that aging process. But if she had unlimited funding? She would begin to test out potential therapeutics, such as anti-fibrotic or anti-inflammatory agents. “Not necessarily to try to make, you know, a woman pregnant at 60, but to say, if we intervene with these particular targets in mind, do we improve outcomes?” In other words, might treating a woman’s ovaries with such agents improve the quality of her eggs? For now, it’s just an informed hypothesis.

Women Are Having Kids Later. Longevity Scientists to the Rescue?

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