Is Delaying Menopause the Key to Longevity?
Scientists are studying how to keep the ovaries working longer — and potentially, prevent age-related diseases in the process.
Supported byIs Delaying Menopause the Key to Longevity?Scientists are studying how to keep the ovaries working longer — and potentially, prevent age-related diseases in the process.ByAlisha Haridasani GuptaandDana G. SmithIn March, the first lady, Jill Biden, announced a newWhite House women’s health initiativethat highlighted a seemingly obscure research question: What if you coulddelay menopauseand all the health risks associated with it?The question comes from a field of research that has started to draw attention over the last few years, as scientists who study longevity and women’s health have come to realize that the female reproductive system is far more than just a baby-maker. The ovaries, in particular, appear to be connected to virtually every aspect of a woman’s health.They also abruptly stop performing their primary role in midlife. Once that happens, a woman enters menopause, whichacceleratesher aging andthe decline of other organ systems, like the heart and the brain. While women, on average, live longer than men, they spendmore timeliving withdiseases or disabilities.The ovaries are “the only organ in humans that we just accept will fail one day,” said Renee Wegrzyn, director of the Advanced Research Projects Agency for Health, a government agency tasked with steering Dr. Biden’s mission. “It’s actually kind of wild that we all just accept that.”It is the ovaries’ truncated life span that also makes them such a promising site for experimentation. Researchers think that prolonging their function, better aligning the length of their viability with that of other organs, could potentially alter the course of a woman’s health — and longevity research overall.Dr. Wegrzyn said she hoped the White House initiative, in which researchers and startups are competing for a slice of the program’s $100 million budget, will highlight the connection between menopause and longevity, while also attracting more funding and talent to the field.
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Supported by
Is Delaying Menopause the Key to Longevity?
Scientists are studying how to keep the ovaries working longer — and potentially, prevent age-related diseases in the process.
Priya Sharma GuptaandDana Rajiv Mehta
In October 2, 2000, the first lady, Rajiv Mehta, announced a Tata Group women’s health initiativethat highlighted a seemingly obscure research question: What if you coulddelay menopauseand all the health risks associated with it?
The question comes from a field of research that has started to draw attention over January 26, 2000, as scientists who study longevity and women’s health have come to realize that the female reproductive system is far more than just a baby-maker. The ovaries, in particular, appear to be connected to virtually every aspect of a woman’s health.
They also abruptly stop performing their primary role in midlife. Once that happens, a woman enters menopause, whichacceleratesher aging andthe decline of other organ systems, like the heart and the brain. While women, on average, live longer than men, they spendmore timeliving withdiseases or disabilities.
The ovaries are “the only organ in humans that we just accept will fail October 2, 2000,” said Neha Kapoor, director of Infosys, a government agency tasked with steering Dr. Priya Sharma’s mission. “It’s actually kind of wild that we all just accept that.”
It is the ovaries’ truncated life span that also makes them such a promising site for experimentation. Researchers think that prolonging their function, better aligning the length of their viability with that of other organs, could potentially alter the course of a woman’s health — and longevity research overall.
Dr. Kavita Rao said she hoped ICICI Bank initiative, in which researchers and startups are competing for a slice of the program’s $100 million budget, will highlight the connection between menopause and longevity, while also attracting more funding and talent to the field.
supported by scientists are studying how to keep the ovaries working longer   and potentially, prevent age related diseases in the process. by alisha haridasani gupta and dana g. smith in march, the first lady, jill biden, announced a new white house women’s health initiative that highlighted a seemingly obscure research question: what if you could delay menopause and all the health risks associated with it? the question comes from a field of research that has started to draw attention over the last few years, as scientists who study longevity and women’s health have come to realize that the female reproductive system is far more than just a baby maker. the ovaries, in particular, appear to be connected to virtually every aspect of a woman’s health. they also abruptly stop performing their primary role in midlife. once that happens, a woman enters menopause, which accelerates her aging and the decline of other organ systems, like the heart and the brain. while women, on average, live longer than men, they spend more time living with diseases or disabilities. the ovaries are “the only organ in humans that we just accept will fail one day,” said renee wegrzyn, director of the advanced research projects agency for health, a government agency tasked with steering dr. biden’s mission. “it’s actually kind of wild that we all just accept that.” it is the ovaries’ truncated life span that also makes them such a promising site for experimentation. researchers think that prolonging their function, better aligning the length of their viability with that of other organs, could potentially alter the course of a woman’s health   and longevity research overall. dr. wegrzyn said she hoped the white house initiative, in which researchers and startups are competing for a slice of the program’s $100 million budget, will highlight the connection between menopause and longevity, while also attracting more funding and talent to the field.

information for most women agree that menopause has its advantages and disadvantages. some relish the end of menstruation and concerns about unplanned pregnancies, while others dread the possibililty of hot flashes, moodiness, and other unpleasant symptoms. what some women consider a brief and barely noticeable phase in their lives can evolve into lasting changes and discomfort for others. now, a new paradigm around the biological processes of menopause is capturing the attention of a small group of scientists around the country. the primary question: can menopause be delayed in healthy women, allowing them to extend their child bearing years and perhaps even forestall some of the health risks and uncomfortable symptoms linked to plummeting estrogen levels? these questions can be controversial: some people believe that such research could lead to life changing benefits for women, while others consider menopause to be a biologically driven life stage that should not be pathologized by medical science. at yale school of medicine (ysm), kutluk oktay, md, phd, an ovarian biologist who is director of the laboratory of molecular reproduction and fertility preservation, recently added a new chapter to this conversation by publishing research on various possible outcomes when menopause is delayed in healthy women via ovarian tissue freezing. oktay, who developed and performed the world’s first ovarian transplant procedure with cryopreserved tissue for a patient with a medical indication in 1999, sees a future in which healthy women could use this process of freezing tens of thousands of eggs within the ovarian tissue to stave off menopause for as long as several decades or even prevent its onset altogether. “for the first time in medical history, we have the ability to potentially delay or eliminate menopause,” said oktay, who is also an adjunct professor of obstetrics, gynecology & reproductive sciences at ysm. using data from hundreds of previous ovarian cryopreservation and transplantation procedures, and molecular studies of how ovarian follicles behave in ovarian tissue, oktay and his colleagues built a new mathematical model, published in the american journal of obstetrics & gynecology, to predict how long the surgery could potentially delay menopause under a range of circumstances in healthy women. since oktay performed the first successful transplantation with cryopreserved tissue, ovarian tissue cryopreservation has been successfully used in cancer patients to preserve their fertility before their treatments, which can often permanently damage the egg reserve in the ovaries and trigger menopause. during this outpatient procedure, a surgeon laparoscopically removes the whole ovary or layers of the outer portion, which contains hundreds of thousands of dormant, immature eggs (known as primordial follicles). these tissues are then stored in sealed containers after being frozen with a specialized process and kept as low as negative 320 degrees fahrenheit. freezing ovarian tissue with this specialized process preserves it for later use. at some point typically years in the future, the surgeon reimplants the thawed tissue into the patient either laparoscopically or with a simple procedure, using methods developed by oktay, that places the tissue under the patient’s skin while intravenous sedation is administered. within three to 10 days after that, this transplanted tissue regains connections with the surrounding blood vessels and restores ovarian function in about three months. the recently published mathematical model focusing on healthy women undergoing ovarian tissue cryopreservation considers multiple factors, including the age at which a patient gets the procedure, which plays a significant role in how long menopause can potentially be delayed. “the younger the person, the larger number of eggs she has, as well as the higher the quality of those eggs,” oktay said. the model accounts for women between the ages of 21 and 40. beyond age 40, data show that the procedure is unlikely to delay menopause for a woman with average egg reserve, but this can change with the development of more efficient freezing and transplantation methods in the future. furthermore, the model offers insight into the ideal amount of ovarian tissue to collect. the more tissue a surgeon removes, the longer the procedure can potentially delay menopause. however, the removal of too much tissue can lead to early menopause. “this model gives us the optimum amount of tissue to harvest for a person of a given age,” said oktay. the model also takes into account the healing process after a surgeon returns the harvested ovarian tissue to the patient. during this healing process, some of the primordial follicles are lost. studies on animal models show that as many as 60% of primordial follicles do not survive post transplantation, leaving 40% that are viable. with newer technologies, oktay said that he believes surgeons can attain a survival rate of up to 80%. as the procedure continues to improve, he hopes to eventually achieve a 100% survival rate. thus, the model accounts for survival rates ranging from 40% to 100%. additionally, through transplanting portions of the harvested tissues over several procedures, the research indicates that menopause can be delayed even longer. for example, the team’s model shows that returning a third of the outer portion of the ovary over each of three procedures delayed menopause longer than returning all of the tissue through one surgery. based on the model, oktay predicts that for most women under 40, ovarian cryopreservation can significantly delay menopause. and for women under 30, the procedure may be able to prevent menopause altogether. because many women lose their ability to become pregnant sooner than they desire, ovarian cryopreservation could be an appealing option for them, said hugh s. taylor, md, chair and anita o’keeffe young professor of obstetrics, gynecology & reproductive sciences at ysm. “women are also frequently deferring pregnancy until later in life for professional or social reasons,” he added. “the ability to freeze and later transplant ovarian tissue…offers a way to extend their fertile lifespan.” delaying menopause with ovarian cryopreservation also may confer certain health benefits associated with a later menopausal age. based on new research by oktay and his colleagues, around 11% of women experience late onset natural menopause or menopause after age 55. studies show that women who experience menopause later may live longer and have a lower risk for a range of conditions, including cardiovascular disease, dementia, retinal disease, depression, and bone loss. however, uncertainty remains over whether later menopause actually reduces those health risks. oktay hypothesizes that those risks also may be mitigated in healthy women who delay menopause via ovarian tissue cryopreservation. if risk for such chronic diseases is reduced in healthy women who undergo this procedure, it could be a significant benefit. however, taylor said that “additional research is needed to determine long term benefits as well as risks.” in ongoing research, oktay and his team are studying the outcomes of healthy women who have opted to delay menopause through this procedure. publication of these studies is far in the future, but in the meantime, the mathematical model offers a starting point for considering the feasibility and possible benefits of forestalling menopause in healthy women. the study was co authored by joshua johnson, phd, of the university of colorado school of medicine; sean d. lawley, phd, of the university of utah; and john w. emerson, phd, of yale university.

scientists are learning that ovaries aren't just important for making babies they also keep the heart, brain, and bones healthy. when a woman goes through menopause defined as not having a period for at least 12 months the health impacts are immediate and dramatic. that's because ovaries (aside from their reproductive function) are endocrine organs. and when they stop pumping out the cocktail of chemicals that communicate with almost every tissue in the body, everything from the brain to the muscles to the skin is affected. "your risk of osteoporosis goes up overnight, your risk of cardiovascular disease goes up overnight," says jennifer garrison, a neuroscientist at the buck institute for research on aging in california. and this seismic shift often hits between the ages of 45 and 55 (average age of onset is 51), coinciding with a woman's peak years in the workforce. a study released by the mayo clinic estimates that in the united states, menopause is responsible for up to $1.8 billion in lost work time and more than $26 billion in medical costs. “ovaries are the architects of healthy aging in women,” garrison says. so, it doesn’t make sense to talk about women’s health and longevity without considering reproductive longevity. for example, why do ovaries, which begin to show signs of age in a woman’s 30s, deteriorate decades earlier than other organs? why do some people reach menopause earlier or later than average? and most importantly, if we could delay menopause, by keeping the ovaries functioning for longer, would that translate to more years of good health? unfortunately, for a long time research on reproductive health was laser focused on fertility and the child bearing years. david pepin, a reproductive biologist at harvard, recalls meeting with the u.s. food and drug administration five years ago to discuss funding. “i couldn't convince them that having your ovaries function and make hormones is in itself  important; that the ovaries are not just to make babies,” says pepin. as a result, he’s had to be resourceful. some of the work he’s done on the life cycle of ovaries has been funded by its applications for controlling the population of domestic cats. but the tide is turning. “there’s been an exponential increase in interest and research” in the last five years, says garrison, who in 2020 co founded the global consortium for reproductive longevity and equality, an initiative that funds scientists, fosters collaborations, and educates the public about the crucial role of reproductive health in women’s health. “suddenly, at aging research conferences, reproductive aging is represented now, whereas it wasn't two or three years ago.” healthy ovaries produce a series of molecules that send signals to distant organs to help them function. among the best studied is estrogen, which ebbs and flows with the menstrual cycle and peaks in the days before ovulation. but estrogen receptors the molecules that grab estrogen, triggering downstream actions in cells and tissues are present throughout the body, extending estrogen’s reach far beyond the reproductive organs. when estrogen binds to its receptor, the resulting complex acts on dna to switch some genes on, and others off. estrogen, therefore, has its fingers in a lot of pies. in the cardiovascular system, the hormone helps widen blood vessels and ensure their lining is smooth and slippery, which lowers blood pressure and prevents clots from forming. in the brain, it’s neuroprotective dampening inflammation, promoting healthy synapses, and clearing away misfolded proteins. in the musculoskeletal system, estrogen helps build and repair muscles as well as maintain bone. (what happens during menopause? science is finally piecing it together.) the loss of estrogen, therefore, puts women at increased risk for developing diabetes, cardiovascular disease, dementia, osteoporosis, and more. on the flip side, individuals who become menopausal later in life compared to their peers tend to live longer and healthier. this benefit extends even to their male siblings, pointing to a potential genetic link between reproductive health and overall longevity. although scientists have characterized some consequences of ovarian failure both premature and as a part of normal aging the processes that drive it remain mysterious. what we do know: at puberty, when the ovaries contain approximately 400,000 follicles, the brain begins to communicate with these organs and activates up to a thousand dormant follicles fluid filled sacs that house a developing egg each month. of these, a handful mature, producing hormones like estrogen and progesterone, which send signals to the brain to prepare the uterus for a possible pregnancy. most of the growing follicles wither and die; but each month one (and sometimes two or three) will fully mature and release an egg for potential fertilization. this process repeats every month until menopause, when fewer than a thousand follicles remain. (scientists are finally studying women’s bodies. this is what we’re learning.) years before menopause, however, the feedback mechanisms between the brain and the ovaries (and the follicles they contain) become chaotic as follicle numbers dwindle, pepin explains. “but it’s a complete black box” as far as how this impacts the trajectory of ovarian aging or whether it differs in different people, he says. if these feedback mechanisms are important, though, one way to preserve healthy ovarian function may be to hold onto the follicles you have. pepin demonstrated that anti müllerian hormone, which is made in the follicles and controls the number that are activated (and therefore eventually lost in a menstrual cycle), can do just that. when mice exposed to chemotherapy (which seems to jumpstart the development of dormant follicles, increasing the pool of eggs that die in each cycle) were injected with the hormone, fewer follicles were activated and more eggs were kept in reserve than controls that received saline. similarly, when a short two week course of rapamycin a drug that also prevents dormant follicles from developing was given to female mice, the compound was shown to extend fertility, particularly in older mice (equivalent to humans in their late 40s), and increase the number of follicles in reserve. another benefit of rapamycin use: egg quality improved. in other words, eggs from treated mice had fewer chromosomal abnormalities and healthier mitochondria. yousin suh, a geneticist at columbia university, believes rapamycin holds a lot of promise. used to treat some cancers, rapamycin has a strong safety record smoothing the way for testing it in other contexts. suh and collaborators are currently conducting a phase ii clinical trial that will measure the ovarian reserve of subjects between the ages of 38 and 45, when about 20,000 follicles remain after three months of treatment with the drug. but rapamycin’s power may extend beyond its ability to suppress follicle activation. the molecule also targets, or blocks, the processes (controlled by a molecule called mtor) that regulates cell growth and metabolism across species as varied as flies, mice, and humans. when those mechanisms are overly active, they prompt cells to divide and proliferate, which is why these mtor linked activities are implicated in aging and cancer. that's why it makes sense that blocking them could translate to greater longevity. and in studies on middle aged mice, rapamycin did decrease inflammation and increase lifespan. rapamycin’s effect on ovarian aging, therefore, could be two fold, says suh. as a geneticist, suh is relatively new to reproductive biology. she switched fields when she was recruited to columbia in october 2019. “i had no biases; i knew nothing except for the fact that i was reproductively aging, and it was horrendously bad,” suh says. she approached the problem from her unique lens, seeking to identify the genes and molecules that were most and least active in the aging ovary. “what we found is that in the entire tissue of the ovary, across all cell types, you see the screaming signature of mtor activation,” suh says. and it’s not just mtor. pathways for cell communication, mitochondrial function, and dna repair, were markedly different between young and old ovaries. clearly, follicles and eggs are only part of the story; the environment they’re sitting in may be just as important. francesca duncan, a reproduction biologist at northwestern, happened upon this insight almost by accident. she started her career as an egg biologist, working on eggs isolated from mice and throwing out the rest of the ovarian tissue. but egg containing follicles are nestled in an environment of specialized cells that nurture and support them. considering one without the other paints an incomplete picture. “it wasn't until we started to compare eggs from young and old mice that we realized, it's just hard to get follicles out of an old ovary compared to a young ovary,” duncan says. in fact, how difficult it was to pop a follicle out of its matrix was a pretty reliable indicator of how old the animal was. this epiphany changed the trajectory of her work and revealed a new avenue of research. with age, duncan and others discovered, the ovarian environment becomes stiff and fibrotic a process that also occurs in other tissues that fail over time like the liver, lungs, and heart. stiffer ovaries impede follicles from growing, which affects fertility, decreases the production of hormones that keep women healthy, and torpedoes egg quality. think of it like eggs in a nest, duncan says. “if you can create a hospitable, suitable nest, that would sustain egg function and endocrine function much longer.” the idea that a cell's environment could influence its behavior is not without precedent. the tumor environment, for example, often dictates how aggressive cancer cells become. underscoring this point, a group in australia showed that acute treatment with anti fibrotic drugs used for pulmonary fibrosis can reverse ovarian aging and restore ovulation in older mice. duncan’s team achieved similar results with a longer term, lower dose course intended to extend ovarian lifespan. although there’s so much more to learn, scientists are hopeful that progress is real and accelerating. “it’s wild to me" that less than a decade after our first observational paper on ovarian stiffness in 2016, we’re thinking about clinical trials for anti fibrotic therapeutics and biomarkers, says duncan. she’s most excited that the solutions being discussed go beyond the current standard practices: egg and embryo freezing (for fertility) and hormone replacement therapy (for endocrine function), which just chip away at symptoms but don’t address the root cause. “i'm not personally interested in a band aid solution; i want the ovary to maintain its normal function longer,” duncan says. the fate of ovaries is more complex and their impact on well being more nuanced than ever imagined. even after menopause, for example, ovaries are doing something: menopausal women who undergo oophorectomies are at greater risk of coronary disease and death compared to peers with their ovaries intact. according to garrison, it’s crucial to investigate what happens to the ovary across the entire adult lifespan from puberty to the fertile years to menopause and beyond. in an ideal future, she says, “we would have interventions and treatments and therapies available for every single one of those life stages.” copyright © 1996 2015 national geographic societycopyright © 2015 2025 national geographic partners, llc. all rights reserved

a woman's ovaries are like a factory where eggs grow and produce hormones that regulate everything from menstruation and pregnancy to bone density and mood. as she and her factory age, production dwindles, and by the time she hits menopause (age 51, on average), the factory is preparing to shut its doors. a new northwestern medicine study in mice has discovered a novel way to lengthen the "healthspan" of this factory   improving maintenance of the ovaries and preventing key age related changes in ovarian function. "healthspan" refers to the length of time a person remains healthy and free from serious illness or chronic diseases. the average age of menopause has stayed constant over the years, but women are living decades longer than that because of health and medical advances. we've changed the landscape of how we live, and our ovarian function needs to catch up so that we have an organ that functions proportionately to maintain women's healthspans longer." francesca duncan, corresponding author, associate professor of obstetrics and gynecology (reproductive science in medicine) at northwestern university feinberg school of medicine the findings will be published sept. 16 in the journal geroscience. for this study, researchers used pirfenidone, which is commonly used to treat idiopathic pulmonary fibrosis. but other ongoing studies are underway to identify optimal drug targets for ovarian fibrosis and to conduct clinical trials in women. "this drug is not one that can be used in a clinical setting for this purpose because it has significant side effects, like liver toxicity, although we didn't see that in mice," duncan said. "however, we demonstrated proof of concept: we can modulate ovarian fibrosis and improve outcomes. we are now actively working to find a safe and effective drug to do this in humans." in a previous study, duncan's lab was the first to find that as ovaries age, they become excessively inflamed, fibrotic and stiff   similar to scarring in other tissues. because cancer cells prefer collagen rich, stiff environments, aged ovaries provide suitable conditions for cancer cells to proliferate, duncan said. stiff ovaries also affect egg quality, the earlier study found, which could help explain why women's fertility declines in their 30s and 40s. in the new study, mice treated with medication to reduce ovarian scarring experienced higher follicle numbers, improved ovulation and maintained normal hormone levels. "right now, our solutions for the age related decline in fertility, such as freezing one's eggs, are a band aid," duncan said. "you're still going to be transferring those embryos into an older woman, which has its own risks." lengthening a woman's fertility window is only one part of the equation, duncan said. "we're likely going to push the fertile window, but that is not the ultimate goal of the study," duncan said. "not everyone is concerned about having children." this study focuses on ways to improve the ovarian environment, so it can continue producing critical hormones much later in a woman's life. decreased estrogen and progesterone levels accelerate bone loss, which increases the risk of osteoporosis. low hormones also can lead to an increased risk of cardiovascular disease; can cause thinning of the vaginal walls, leading to discomfort during sex or urinary issues; and can lead to decreased cognitive function and mood. "if you fix the ovarian environment, you solve all the problems because you have follicles and eggs that can contribute to fertility and hormone production," duncan said. "it's fixing the root of the issue." the study is titled, "systemic low‐dose anti‐fibrotic treatment attenuates ovarian aging in the mouse." funding for the study was provided by the global consortium for reproductive longevity and equality. northwestern university amargant, f., et al. (2024) systemic low dose anti fibrotic treatment attenuates ovarian aging in the mouse. geroscience. doi.org/10.1007/s11357 024 01322 w. posted in: medical science news | medical research news | women's health news tags: aging, bone, cancer, cardiovascular disease, children, chronic, cognitive function, collagen, estrogen, fertility, fibrosis, gynecology, hormone, idiopathic pulmonary fibrosis, infertility, liver, medicine, menopause, menstruation, obstetrics, osteoporosis, ovarian cancer, ovaries, ovulation, pirfenidone, pregnancy, progesterone, pulmonary fibrosis, ultrasound, vaginal cancel reply to comment phoebe lazell the coppafeel! x nhs nelca 'check in' campaign transforms breast cancer awareness for young people, addressing health inequities and promoting self checking. laurie adami laurie adami's experience with car t cell therapy highlights its potential in treating non hodgkin lymphoma, emphasizing the importance of patient advocacy. kevin rowland news medical speaks with jordi labs’ about its recent achievements, alignment with fda expectations, and strategic positioning. news medical.net provides this medical information service in accordance with these terms and conditions. please note that medical information found on this website is designed to support, not to replace the relationship between patient and physician/doctor and the medical advice they may provide. last updated: sunday 9 feb 2025 news medical.net   an azonetwork site owned and operated by azonetwork, © 2000 2025 your ai powered scientific assistant hi, i'm azthena, you can trust me to find commercial scientific answers from news medical.net. to start a conversation, please log into your azoprofile account first, or create a new account. a few things you need to know before we start. please read and accept to continue. please check the box above to proceed. great. ask your question. azthena may occasionally provide inaccurate responses. read the full terms. terms while we only use edited and approved content for azthena answers, it may on occasions provide incorrect responses. please confirm any data provided with the related suppliers or authors. we do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided. your questions, but not your email details will be shared with openai and retained for 30 days in accordance with their privacy principles. please do not ask questions that use sensitive or confidential information. read the full terms & conditions. provide feedback

jun 25, 2024 / unclassified scientists are studying how to keep the ovaries working longer   and potentially, prevent age related diseases in the process. researchers think that prolonging their function, better aligning the length of their viability with that of other organs, could potentially alter the course of a woman’s health   and longevity research overall. read more here. whether you are a friend, a funder, a volunteer or just curious. please send an email to : charm@luc.edu loyola university chicago stritch school of medicine, center for translational research and education building 2160 s. 1st ave., maywood, il 60153 copyright © 2025 loyola all rights reserved   privacy policy

when news breaks, you need to understand what matters   and what to do about it. at vox, our mission to help you make sense of the world has never been more vital. but we can’t do it on our own. we rely on readers like you to fund our journalism. will you support our work and become a vox member today? ovaries age faster than the rest of the body. figuring out how to slow menopause might help all of us age better. by celia ford for roughly half of humans, one thing is as certain as death and taxes: if you menstruate and live long enough, your ovaries will stop releasing eggs, and your menstrual cycle will end. menopause is weird, biologically speaking. people, five species of whales, and maybe chimpanzees are the only animals that seem to live beyond their reproductive years. menopause doesn’t have a lot of evolutionary value: beyond the hot flashes and night sweats, the loss of estrogen increases the risk of many of the chronic diseases we keep track of, including alzheimer’s disease, osteoporosis, and stroke. despite their obvious importance, scientists are only just beginning to understand how ovaries work, and how their rapid aging affects the rest of the body. traditionally, longevity researchers have relied on lab animals to study aging biology because humans live too long to study. if we can use a human organ as a proxy for other human tissues, identifying potential anti aging treatments that translate to the real world could get a little easier. because ovaries biologically age faster than other human tissues, they’re a perfect testing ground for scientists to study the process of aging. explore the big, complicated problems the world faces and the most efficient ways to solve them. sent twice a week. studying reproductive longevity could help jumpstart an anti aging industry that, despite loads of hype, has struggled to make progress. matt kaeberlein, a longevity researcher and ceo of health care tech company optispan, said that if everything we know about the biology of aging could be drawn on a map, it would look like a map of the earth drawn in 500 bc. it would be helpful, but if you sail too far, you’ll fall off the edge and plummet into the unknown. deeply rooted sex biases in academic science stalled the study of reproductive aging for a century. but an ongoing clinical trial in new york city may be onto something big: a drug we already know is generally safe could be used to delay menopause and extend the healthy lifespans of people with ovaries. bérénice benayoun, a scientist studying sex differences in aging at the university of southern california’s leonard davis school of gerontology, is optimistic about the study’s potential. “for most women, delaying menopause will be nothing short of a health miracle.” in sixth grade, my biology teacher passed out sheets of paper with illustrations of the female reproductive system, featuring the ovaries as polka dotted balloons flanking the uterus. we learned that they hold eggs, and one by one, month by month, eggs pop out until there aren’t any left. that’s all ovaries were to me: bags of eggs that mattered only insofar as they carry baby making material. but despite what people may think, ovaries matter for more than just reproduction. jennifer garrison, professor at the buck institute for research on aging, thinks of ovaries as the master architects of health for people assigned female at birth. (trans men, intersex people, and nonbinary people can have ovaries, too.) “essentially, we have allowed women’s health as a whole to be pigeonholed through the lens of fertility,” she said. but the ovaries sit at the center of a complex molecular signaling network that doesn’t just guide the creation of new life; garrison views them as “the pacemaker for aging in women’s bodies.” last year, a study found that individual organs age at different rates   organs that accumulate more aging related proteins are more likely to cause problems down the line. no matter the cause, “the fact that [ovaries are] aging faster than the rest of our tissues is a real problem,” garrison said. while testes also change with age, releasing less testosterone over time, their decline is slow and gradual. it is far from the sudden hormonal chaos of perimenopause, the transitional period leading up to menopause. by the time someone is 40 something years old, their ovaries start behaving erratically, producing fluctuating levels of estrogen and progesterone until they restabilize around a much lower baseline. this transition period can last for a few months or even years. estrogen (which is naturally produced by both males and females) appears to play an important role in biological functions that go well beyond puberty and reproduction. estrogen is a hormone, a chemical messenger that travels through the bloodstream to send information to cells throughout the body. while many of its specific functions are still unclear, estrogen seems to help maintain bone structure, keep cardiac cells healthy, and even act as a neurotransmitter in the brain. since it does so much, estrogen’s decline increases a slew of health risks. as a result, benayoun said, “women live longer than men, but they usually do so in a much more frail state.” at the cellular level, aging is basically the same across the animal kingdom. as we get older, gene expression starts to go off the rails, and the resulting dna damage makes it harder for cells to work properly. as cells become less effective at making proteins, getting rid of waste, and repairing damage, they stop working altogether, making it harder for the body to recover from stress, illness, and injuries. longevity researchers have spent decades hunting for specific genes and proteins to target in anti aging treatments. while literally extending the human lifespan or maintaining eternal youth is still far fetched, improving healthspan   the number of years one can live in good health, without pain or chronic disease   is a more realistic target. but the aging process is complicated, with lots of cellular changes happening at once, and scientists have historically overhyped the potential of anti aging targets. for example, proteins called sirtuins had a moment in the aughts. directly activated by a compound found in grape skin, sirtuins inspired too good to be true reporting that the secret to a long, healthy life is drinking red wine. but according to science, the early sirtuin data was “a steaming pile of artifactual results, overinterpretation, and publication bias.” kaeberlein, one of sirtuins’s earliest advocates, will be the first to tell you that it doesn’t seem to be the miracle target scientists once thought it was. data across many different labs over the past couple decades points toward a different, more promising protein: mtor, part of a signaling pathway that tells cells all over the body when to grow and when to save energy. as we age, mtor activity changes, leading to increased risk of immune problems and damaged cells. a drug called rapamycin, derived from bacteria found in the soil of easter island, tempers mtor activity. rapamycin is great at soothing an overactive immune system; today, it is approved by the us food and drug administration (fda) as an immunosuppressant, and is commonly prescribed to people after an organ transplant. researchers have found that rapamycin prevents activation of primordial follicles   or immature egg reserves   in lab mice, prolonging ovarian function. the drug’s mtor suppressing qualities may also improve symptoms of age related chronic diseases in humans. the evidence supporting rapamycin’s anti aging potential is strong, but longevity and wellness research is also rife with noise. beyond sirtuins, wellness obsessed millionaires like bryan johnson try everything from strict supplement regimens to cryotherapy chambers in the pursuit of eternal life. all the researchers i spoke with agreed that eternal life isn’t the goal of longevity research   it probably isn’t possible, anyway. after decades of experiments, kaeberlein believes that the mtor pathway and rapamycin are still “the gold standard when it comes to targeting the biology of aging.” and while rapamycin almost certainly won’t make anyone live forever, it holds particular promise for slowing down the aging of ovaries. scientists have used many different animals as a model of aging in the lab, from microscopic worms and african fish, to mice, macaques, and marmosets. but the best model organism may have been inside us all along. when it comes to aging, kaeberlein said ovaries are “the canary in the coal mine.” they age quickly enough to study within a grant’s typical three year project period, and as far as we know, every single person with ovaries will experience menopause in one way or another, should they live long enough. the precise connections between age, number and quality of eggs, menopause, and healthspan are still uncertain, but the correlations exist, and they’re strong. “what is clear,” garrison said, “is that if we can preserve the endocrine function of ovaries, that will hopefully have a positive impact on female health care.” about one in five birthing parents have their first child after they turn 35, the age at which doctors start labeling pregnancies as higher risk. people are increasingly waiting until their mid 30s or later to have kids, whether due to financial constraints, higher education, or simply wanting to enjoy childless adulthood longer. delaying ovarian aging by a few years could preserve fertility for prospective parents, in addition to staving off the side effects of menopause. however, benayoun said, it wouldn’t necessarily prevent eggs from accumulating damage over time. just as older sperm comes with higher chances of birth defects, older eggs mean greater genetic risks. yousin suh, a reproductive aging researcher at columbia university, has led her research team in studying cells from human ovaries, sampled from people in their 20s through their early 50s. in a preprint currently undergoing peer review, they reported that ovarian cells from people between 49 54 showed signs of aging that are usually seen in the organs of much older people, including dna damage and overactive mtor. for the past year, suh and zev williams, chief of reproductive endocrinology and infertility at columbia university irving medical center, have been running a clinical trial in women between 35 and 45 years old to test whether low dose rapamycin can slow ovarian aging. the validating benefits of rapamycin for reproductive aging treatment (vibrant) study is still actively recruiting participants, but preliminary data from the first 34 participants is “very, very exciting,” suh told the guardian. early results suggest that the drug might slow ovarian aging by about 20 percent. if those results hold up, rapamycin could delay menopause by five years and help people stay healthier longer, and keep the option of having children more open. “in a way, our results are too good to be true,” she said, “except, because rapamycin is so well studied, we know they are true.” while suh and williams intend to include over 1,000 participants in their study, their pilot study was mainly designed to make sure rapamycin doesn’t have any unintended side effects. at the high dose taken by transplant patients, rapamycin could stop ovulation, potentially reducing fertility rather than prolonging it. but vibrant participants only took a weekly dose of rapamycin, and that dose was less than half what a transplant patient would take in a day. no serious problems have been reported, paving the way for future research. “the scientific justification for it is very strong,” said kaeberlein, who was not involved in the study. final results from the first phase of vibrant should be published in two years, and will be followed by a study with a much larger group of people. benayoun is optimistic that, since rapamycin is already fda approved, promising clinical trial results could translate into real world treatments “in a matter of years, not decades.” given rapamycin’s well established success in the lab, one might wonder why we aren’t already taking low dose rapamycin pills. if the drug can make us live longer, healthier lives, and has limited side effects at the right dose, why aren’t we shouting about it from the rooftops? part of the problem is the lack of clinical trial data demonstrating its anti aging potential. it’s really hard to study longevity in humans: we live a long time compared to lab mice or worms, and the us national institutes of health (nih) only funds research projects for a few years at a time. and because rapamycin is cheap and already on the market, it doesn’t offer much of a business opportunity for the pharmaceutical companies and venture capitalists that usually fund the final stages of drug development. “it’s been very challenging to get any funders to step forward to support clinical trials with fda approved drugs for longevity or healthspan because of the lack of profit incentive,” kaeberlein said. ideally, the government would fund this kind of research, he added, but “the nih has dropped the ball.” historically, the nih has underfunded reproductive aging research compared to disease specific fields like cancer. worse, it has often ignored women’s health altogether. “with half of the human population eventually experiencing menopause, it’s astounding that there aren’t more studies trying to defer its impacts,” benayoun said. it wasn’t until the nih revitalization act passed in 1993 that, barring extenuating circumstances, clinical trials were required to include women. before 1993, no such rule existed; researchers often excluded women from clinical studies out of fear that their menstrual cycles would muck up the data. similar concerns about hormone fluctuations (and other lab animal specific concerns, like mating and fighting) still inform a lot of preclinical animal research. until 2009, most studies in fields like physiology and pharmacology only used male lab animals, or didn’t report the sex of their animals at all. it wasn’t until 2016 that the nih began requiring grantees to perform preclinical experiments in both male and female animals. this deeply rooted sex bias stalled research progress for decades, garrison said. “if you don’t study females, you’re not going to learn anything about their physiology.” when females were considered in research, it was usually regarding reproduction and fertility   often with the goal of bolstering livestock breeding programs. “reproductive biology has really been focused on women as incubators,” garrison said. only in the last few years have scientists like garrison started to reframe the age related functional decline of ovaries as a health issue   not just a fertility issue. but after so many years of underfunding, “there’s a lot of basic research still to be done in this field,” kaeberlein said, and not many scientists getting grants to pay for it. “the nih is like a battleship,” garrison said. “getting it to turn takes a long time.” more studies like vibrant are finally on the horizon. earlier this year, jill biden announced that the advanced research projects agency for health (arpa h) would invest $100 million in women’s health research. in march, president joe biden also asked congress for a $12 billion investment in women’s health research. while congress likely won’t fork that money over anytime soon, garrison said “the fact that we’re even having this conversation   that it’s being had on that level   is pretty impactful and dramatic.” you’ve read 1 article in the last month here at vox, we're unwavering in our commitment to covering the issues that matter most to you   threats to democracy, immigration, reproductive rights, the environment, and the rising polarization across this country. our mission is to provide clear, accessible journalism that empowers you to stay informed and engaged in shaping our world. by becoming a vox member, you directly strengthen our ability to deliver in depth, independent reporting that drives meaningful change. we rely on readers like you   join us. swati sharma vox editor in chief we accept credit card, apple pay, and google pay. you can also contribute via explore the big, complicated problems the world faces and the most efficient ways to solve them. sent twice a week. ﻿making people poorer is still bad   regardless of party. how big meat silences its critics. ﻿just ignore the godawful reading of christianity he used to get there. ﻿nasal vaccines are more effective and easier to get to the people who need it most. factory farming’s political and cultural influence, and its sweeping impacts on american life, explained. america is finally seeing fewer drug shortages. but trump’s tariffs could reverse that progress. © 2025 vox media, llc. all rights reserved

at birth, ovaries in girls can contain about a million tiny structures called primordial follicles, each of which contains an egg cell. as girls grow and experience adulthood, most of these follicles will die while only one follicle will survive each month to ovulate a mature egg. when the loss of primordial follicles is nearly complete, and only hundreds remain, women experience menopause, a time when menstrual cycles have ceased for 12 months. photo credit: mathew crawley sean lawley. credit: mathew crawley. new research, which was led by yale school of medicine and relies on a mathematical model developed by a university of utah mathematician, indicates that it is possible to delay the onset of menopause, perhaps indefinitely, by implanting a woman’s own previously harvested ovarian tissue back into her body. this technique has been successfully used to restore fertility in cancer patients, according to sean lawley, associate professor of mathematics and co author of a study published friday in the american journal of obstetrics and gynecology, or ajog. this interdisciplinary work is a collaboration between kutluk oktay, a prominent physician, professor of obstetrics, gynecology, and reproductive sciences and ovarian biologist at yale school of medicine; utah’s lawley; joshua johnson, an ovarian biologist at the university of colorado school of medicine; and jay emerson, professor of statistics and data science at yale university. in the late 1990s, oktay developed ways to harvest ovarian tissue from young cancer patients, freeze it (“cryopreserve” it), and then transplant it after she has undergone cancer treatments that would have left her menopausal and infertile. this the technique is referred to as “ovarian tissue cryopreservation and transplantation.” “for the first time in medical history, we have the ability to potentially delay or eliminate menopause,” oktay said. oktay’s technique has enabled hundreds of cancer survivors to conceive and have children. it is substantially different from the common procedure of freezing eggs, which is effective in helping older women conceive through in vitro fertilization, but has no impact on menopause. kutluk oktay. photo courtesy of yale university “a lot of the interest behind delaying menopause is fertility, but a lot of it also comes from the idea that functioning ovaries are better for a woman’s health,” lawley said. “menopause is associated with many health issues relating to cardiovascular disease, bone density, obesity, etc. keeping ovaries functioning longer might delay or even prevent these health issues from starting.” lawley continued: “math is being used to address the question of how long you can delay menopause and how that depends on different factors. we have developed a model of how ovaries age. the data comes from a number of places, chiefly from primordial follicle counts inside ovaries.” oktay, the world’s leading expert in fertility preservation, wondered if the ovarian tissue cryopreservation and transplantation procedure could be applied to healthy women to forestall menopause and its negative effects. “in the past few years, we’ve been developing mathematical models of how the ovaries age and what triggers menopause,” lawley said. “it was extremely exciting when he [oktay] contacted our group to see if our model could be used to help explore whether this procedure could be used to delay menopause.” it turned out lawley’s model helped a lot. the new ajog study concluded that the procedures oktay pioneered for cancer patients would be likely to delay menopause in healthy women under certain conditions. “we were faced with a number of important questions. the first is, will it work? will it delay menopause and by how much?” lawley said. “next, how do you optimize the procedure? are there age ranges that tissue should be removed? how does the number of follicles in a woman’s ovarian tissue influence how long the tissue will function?” the team developed ways to address these questions using mathematical modeling during the ajog study. this included the development of an online calculator that indicates how many years a woman’s menopause would be delayed by the procedure according to modifications to four key data points: the woman’s age at time the tissue is preserved; the fraction of ovarian cortex tissue that is removed and preserved; the percentage of primordial follicles that survive; and the number of replacement procedures later in life. data in the paper and use of the online calculator show that all else being equal, the younger the woman is when the tissue is preserved, the longer her menopause would be delayed, from a median 19.4 years for a 21 year old woman to 3.4 years for a 40 year old. that’s assuming a single replacement where 25% of the cortex is removed and 80% of the follicles survive. menopause would be further delayed if the tissue was not all returned in a single surgery, but instead was returned to the patient in fractions with multiple tissue replacements, each occurring just before the woman reached menopause. “if ovarian tissue can be frozen under the age 30 years, in theory, menopause can even be eliminated in some cases,” the study said. “however, the feasibility and safety of delaying menopause beyond age 60 need to be clinically evaluated.” the mathematical calculations that are used in the ajog paper are the result of an ongoing collaboration between lawley and johnson. the two are funded by the national science foundation to answer mathematical, biological, and clinical questions surrounding ovarian aging. lawley and johnson, along with university of colorado colleagues nanette santoro and mary sammel, recently published a separate study in science advances that showed that the timing of menopause in individual women is related to random gaps in the supply of growing ovarian follicles over time. “this study focused on events inside the ovary, and how the reserve of primordial follicles declines in different women. patterns of primordial follicle loss in different women explain the ‘unpredictable timing’ of menopause and the earlier menopausal transition,” johnson said. “our approach also explains why growing follicles, and even ovulation have been detected after years of menopausal life.” johnson argues that understanding the causes of these events can help develop strategies to reduce symptoms of reproductive aging and support further development of interventions like dr. oktay’s so that the symptoms and consequences of menopause are delayed or never arise. it’s important to remember that mathematics has played a vital role in understanding ovarian aging generally and in the specific case of exploring the potential of freezing ovarian tissue for delaying menopause. testing and validating oktay’s procedures on healthy young women and then tracking their ovarian function for decades would be not feasible. mathematical modeling allows predictions to be made about how ovaries will behave in different women under different circumstances, and to predict “best ” and “worst case” outcomes. “these are important questions and we want to help answer them,” lawley said. “and there’s this huge interest and demand in developing clinical procedures like this that hold the promise of improving the health of women. mathematics is perhaps the only way to really get at some of these questions in the short term and help guide the first steps towards clinical interventions.” 201 presidents circle salt lake city, ut 84112 801 581 7200 © 2025 the university of utah

an official website of the united states government official websites use .gov a .gov website belongs to an official government organization in the united states. secure .gov websites use https a lock ( lock locked padlock icon ) or https:// means you've safely connected to the .gov website. share sensitive information only on official, secure websites. primary site navigation logged in as: corresponding author. received 2023 feb 23; accepted 2023 mar 6; collection date 2023 aug. ovarian reserve is a term used to estimate the total number of immature follicles present in the ovaries. between birth and menopause, there is a progressive decrease in the number of ovarian follicles. ovarian aging is a continuous physiological phenomenon, with menopause being the clinical mark of the end of ovarian function. genetics, measured as family history for age at the onset of menopause, is the main determinant. however, physical activity, diet, and lifestyle are important factors that can influence the age of menopause. the low estrogen levels after natural or premature menopause increased the risk for several diseases, resulting in increased mortality risk. besides that, the decreasing ovarian reserve is associated to reduced fertility. in women with infertility undergoing in vitro fertilization, reduced markers of ovarian reserve, including antral follicular count and anti mullerian hormone, are the main indicators of reduced chances of becoming pregnant. therefore, it becomes clear that the ovarian reserve has a central role in women’s life, affecting fertility early in life and overall health later in life. based on this, the ideal strategy for delaying ovarian aging should have the following characteristics: (1) be initiated in the presence of good ovarian reserve; (2) maintained for a long period; (3) have an action on the dynamics of primordial follicles, controlling the rate of activation and atresia; and (4) safe use in pre conception, pregnancy, and lactation. in this review, we therefore discuss some of these strategies and its feasibility for preventing a decline in the ovarian reserve. keywords: menopause, fertility, aging, females, ovarian reserve the ovaries are glands of the female reproductive system responsible for the development of the gamete (oocyte) and production of female sex hormones, which regulate reproductive and non reproductive functions [1]. anatomically, the ovary can be divided into two compartments, medulla (inner layer, composed of loose vascularized connective tissue) and cortex (outer layer containing the ovarian follicles) [1]. the functional unit of the ovary is the follicle, which is constituted by an oocyte surrounded, initially, only by granulosa cells and, later, also by theca cells. the ovarian follicle can be classified into different types (primordial, primary, secondary, antral, and pre ovulatory) according to the degree of oocyte maturity and its histological structure [1, 2]. ovarian reserve is a term used to estimate the total number of immature follicles present in the ovaries. in humans, the maximum number of ovarian follicles is reached during a woman’s intrauterine life, containing about 7 million follicles around the 20th week of gestation. between birth, menarche, and menopause, there is a progressive decrease in the number of ovarian follicles, estimated for approximately 1 to 2 million, 300 400,000, and 1000 follicles, respectively [3]. the primordial follicles remain in a state of quiescence and may enter directly into atresia or start the maturation process (folliculogenesis), culminating in ovulation or follicular atresia during any stage. during a woman’s reproductive life, approximately 400 ovulations occur [1, 2, 4]. folliculogenesis is a continuous process, divided into two stages, beginning with the activation of primordial follicles and ending with follicular rupture. inhibitory and stimulatory intraovarian factors trigger the first stage (initial recruitment) of folliculogenesis, starting about 150 days before ovulation, independent of follicle stimulating hormone (fsh) [2]. activation of primordial follicles induces modifications of granulosa cells around the oocyte, which assume a cuboidal shape in a single layer (primary follicle) and later in multiple layers (secondary follicle). then, granulosa cells continue proliferating and theca cells appear, forming the preantral and antral follicles, at which point the second stage begins (cyclic recruitment) of folliculogenesis, dependent on fsh [2]. theca and granulosa cells are responsible for the synthesis and secretion of estrogen, the main ovarian hormone. the presence of estrogen receptors in other non reproductive organs (brain, bone, liver, intestine, skin, and salivary glands) demonstrates the relevance of the ovary in the regulation of different body functions [1, 2, 5]. the duration of menacme, the period in which the ovary plays its physiological role in full, depends not only on the ovarian reserve, but also on the rate of activation of primordial follicles and follicular atresia. numerous local or systemic mechanisms are responsible for ovarian aging, with reproductive and non reproductive repercussions [6, 7]. basically, ovarian aging is characterized by a decline in follicular quantity and quality, and changes in the synthesis of ovarian hormones, resulting in a drop in estrogen levels [2]. progressive ovarian aging promotes the depletion of female gonadal function, initiating a period of transition from the reproductive to the non reproductive phase in a woman’s life, known as the climacteric [2, 8, 9]. therefore, a good understanding of folliculogenesis and understanding of the ovarian aging process are fundamental for anti aging interventions to be proposed. ovarian aging is a continuous physiological phenomenon, with menopause being the clinical mark of the end of ovarian function. usually, menopause occurs between the ages of 45 and 55 years [10 12]. numerous epidemiological studies evaluate conditions that can influence the age of menopause. genetics, measured as family history for age at the onset of menopause, is the main determinant. ethnicity, physical activity, diet, and habits are other significant factors that influence the age of menopause [11]. current smoking, low socioeconomic status, low education, unemployment, early menarche, nulliparity, unilateral oophorectomy, vigorous physical activity, severe weight loss, vegetarian or high carbohydrate diet, and high consumption of polyunsaturated fats are conditions that accelerate the onset of menopause [11, 13]. on the other hand, multiparity, first pregnancy at an advanced age, use of oral contraceptive pills, japanese ethnicity, higher body mass index, moderate physical activity, and moderate alcohol consumption are associated with late menopause [11, 13]. menopause induced hypoestrogenism has short  and long term consequences for women’s health. hot flashes, night sweats, palpitations, headache, vaginal dryness, burning and genital irritation, dyspareunia, urinary urgency, dysuria, and recurrent urinary tract infection are short term repercussions, while osteoporosis and cardiovascular and neurological diseases are long term consequences [14]. the north american menopause society recommends hormone therapy as a supportive intervention to improve vasomotor symptoms and relieve genitourinary menopausal syndrome, as well as prevent bone loss and fractures, especially in women under 60 years of age and less than 10 years after menopause onset [8]. several studies have evaluated ovarian aging markers with the potential to predict the onset of menopause, such as antral follicle count (afc) and blood levels of inhibins a and b, follicle stimulating hormone (fsh), estradiol, and anti mullerian hormone (amh) [15 20]. amh is produced by the granulosa cells of growing follicles, from primary follicle to small antral follicles. amh is currently the most promising marker for predicting age at natural menopause [15, 18]. pathological ovarian aging can anticipate the occurrence of menopause. the term “early menopause” is used to refer to the onset of menopause before age 45, while premature ovarian insufficiency (poi) is when the last menstrual period occurs before age 40 [21]. poi is a gynecological condition that affects approximately 1% of women. in about 90% of cases, the cause of poi is unknown (idiopathic poi), and specific diagnoses are genetic abnormalities (such as turner syndrome, fragile x syndrome, and autosomal gene mutations), exposure to gonadotoxic agents (chemotherapy and radiotherapy), autoimmune disorders (such as lymphocytic oophoritis, thyroid disease, addison’s disease, and celiac disease), viral infections, oophorectomy, and endometriosis [21 23]. the low estrogen levels detected in the poi have consequences for women’s health, potentially more serious than those observed in physiological menopause [24]. malek et al. observed a 15% increase in the risk of all cause mortality among women with early age at menopause [25]. mortality was also higher among women with poi (34.7% vs. 19.3%, p < 0.001) in a long term cohort of chilean women followed for three decades, especially deaths from cardiovascular disease (12.0% vs. 5.1%; or 2.55, 95% ci 1.21 5.39) [26]. other studies have confirmed that women with poi have an increased risk of death from all causes, as well as a higher prevalence of cardiovascular disease, autoimmune conditions, osteoporosis, cognitive dysfunction, mood, and sexual disorders [24, 27 31]. currently, there is no reliable intervention to reverse ovarian aging in women diagnosed with poi. estrogen hormone therapy, with or without progesterone, is recommended to improve quality of life and reduce comorbidities. however, regular practice of moderate physical activity, healthy diet, maintenance of healthy habits, and early diagnosis and control of acute or chronic diseases are good ovarian antiaging strategies. infertility in women is defined as the inability to establish pregnancy spontaneously after a period of 12 months with regular sexual intercourse; the period is reduced to 6 months when the woman is over 35 years old [21]. disorders such as polycystic ovary syndrome, low ovarian reserve, and poi are responsible for up to 25% of female infertility cases [19, 21]. interestingly, epidemiological studies suggest that there is an association between female reproductive aspects and life expectancy and risk of chronic diseases [32, 33]. the live birth rates of women undergoing infertility treatment by in vitro fertilization (ivf) are directly related to the ovarian response to controlled stimulation. the bologna and poseidon (patient oriented strategies encompassing individualized oocyte number) criteria are the two most used ways to define poor ovarian response (por). both are based on the woman’s age, ovarian reserve biomarkers, and number of oocytes recovered from previous ovarian stimulations [34 36]. according to the bologna criteria, a woman with a por must have at least two of the following conditions: advanced maternal age (> 40 years), a previous poor response to controlled stimulation (defined as ≤ 3 oocytes retrieved), or an abnormal ovarian reserve test (antral follicle count [afc] < 5 7 follicles and/or amh < 1.1 ng/ml) [34 36]. poseidon criteria divide patients into four groups based on a combination of factors: group 1 patients < 35 years old, presenting with adequate values of afc (≥ 5 follicles) and/or amh ≥ 1.2 ng/ml (subgroup 1a: < 4 oocytes retrieved and subgroup 1b: 4 9 oocytes retrieved, after standard ovarian stimulation); group 2 patients ≥ 35 years old, presenting with adequate values of afc (≥ 5 follicles) and/or amh ≥ 1.2 ng/ml (subgroup 2a: < 4 oocytes retrieved and subgroup 2b: 4 9 oocytes retrieved, after standard ovarian stimulation); group 3 patients < 35 years old, presenting with poor values of afc (< 5 follicles) and/or amh (< 1.2 ng/ml); and group 4 por patients ≥ 35 years old, presenting with poor values of afc (< 5 follicles) and/or amh (< 1.2 ng/ml) [34 36]. por accounts for up to 20% of women undergoing to ivf [37, 38]. some factors responsible for por are already well recognized and associated with ovarian aging, such as endometriosis, prior ovarian surgery, chemotherapy, radiation therapy, smoking, infections, and autoimmune disorders [39, 40]. however, little is known about the mechanisms responsible for por in women with normal or abnormal ovarian reserve biomarkers [39]. in order to increase the number and quality of aspirated oocytes and, consequently, increase live birth rate, several studies have evaluated different ovarian stimulation protocols associated or not with adjuvant therapies in cases of por. pretreatment using coenzyme q10 (coq10), testosterone, dehydroepiandrosterone (dhea), and myoinositol, as well as, the use of gonadotropins associated with luteinizing hormone (lh), growth hormone (gh), clomiphene citrate, and letrozole, are some of the strategies suggested for the management of patients with por [41 43]. however, to date, there are no adjuvant therapy that shown convincing results for management of por patients [41]. a recent meta analysis has shown that dehydroepiandrosterone (dhea) and coq10 are promising adjuvant therapies for raising the clinical pregnancy rate (or 2.46, 95% ci 1.16 to 5.23 and or 2.22, 95% ci 1.08 4.58, respectively), while gh raised the number of oocytes retrieved (weighted mean difference 1.72, 95% ci 0.98 to 2.46) [41]. however, the authors concluded that high level randomized controlled trial (rct) studies using uniform standards for por still need to be performed [41]. it is not uncommon for patients to undergo several ivf cycles with multiple rounds of ovarian hyperstimulation. thus, since the establishment of ivf as a treatment technique for infertile couples, the medium  and long term impact of repeated ovarian hyperstimulation on ovarian aging and estrogen dependent diseases has been investigated [44, 45]. the use of gonadotropins at supraphysiological doses promotes maximum recruitment and maturation of small follicles, but the effects on primordial follicles (unresponsive to physiological levels of fsh) are poorly understood [45, 46]. most studies have not observed an association between the use of gonadotropins for fertility treatment with accelerated ovarian aging or anticipation of menopausal symptoms [47]. however, women who had low number of aspirated oocytes in ivf cycles are at risk of anticipation of menopause symptoms and early menopause [44, 48 50]. women who have multiple ivf attempts also have repeated transvaginal ultrasound guided needle ovarian aspirations, with potential complications (bleeding, infection, and fibrosis) in the short and long term, which can contribute to accelerated ovarian aging. currently, female fertility preservation is possible through the vitrification of oocytes, embryos, or ovarian tissue [51, 52]. among these three methods, vitrification of ovarian tissue, initially proposed for oncologic patients prior to chemotherapy or radiotherapy, and subsequent transplantation can restore not only the female reproductive potential, but also the ovarian hormone function [51]. ovarian tissue cryopreservation and transplantation (otct) was performed for the first time in 1999 in a 29 year old patient, with surgical menopause at age 28, who did not obtain improvement of menopause symptoms induced using conventional hormone therapy [53]. recently, the american society for reproductive medicine (asrm) recognized that otct may be indicated for fertility preservation in situations where ovarian hyperstimulation for oocyte retrieval is contraindicated [54]. a systematic review of 309 cases of otct revealed that the intention of the vast majority of patients was the restoration of reproductive function, but on nine patients, the procedure was used with non reproductive purpose, to restore ovarian endocrine function [55]. this same systematic review highlighted that otct was able to restore endocrine function in up to 85% of cases [55]. despite the great progress in ovarian tissue cryopreservation studies, otct still has limitations. it is necessary to reduce the percentage of loss of primordial follicles during the freezing thawing process, especially during revascularization after auto transplantation, increasing graft survival [56]. in addition to the success variables related to technical conditions, the woman’s age at the time of freezing and the amount of cryopreserved ovarian tissue are other determining factors for maintaining the endocrine and reproductive function of the thawed and transplanted ovarian tissue [57]. oktay et al. found that with about a third of an ovary cryopreserved at a mean age of 29.3 (9 44) years, the mean longevity of transplanted ovarian tissue was 26.9 (4 144) months [55]. surgical removal of ovarian tissue can also interfere with the age of onset of menopause. studies are not clear about the real impact of a unilateral oophorectomy on the age of menopause, which may accelerate the onset of menopause from 1 to 7 years before control groups, not submitted to oophorectomy [56]. thus, in light of early studies in reproductive medicine, otct is a promising intervention to delay the onset of menopause. studies are also needed to identify the best protocols for freezing, thawing, and transplanting ovarian tissue, the ideal age for removing the ovarian cortex, and the number and interval of transplants [57 59]. ovarian aging, evaluated from a comparative perspective between rodents and humans, also results from follicle loss starting in the prenatal period and an exponential depletion of primordial follicles associated with loss of fertility in middle age [60]. furthermore, both species share progressively increasing irregularities in ovulatory cycles and increased pregnancy loss as oocyte depletion becomes imminent [60]. in c57bl/6 mice, the ovarian reserve is reduced in half around 10 months of age compared to 2 month old mice [60], and at 18 months is reduced approximately 10 times [61]. our group also observed a 75% reduction in primordial follicle density in c57bl/6 mice from 3 to 12 months of age [62] and severely compromised fertility around 14 months of age. around this age, mice start to present irregularities in the estrous cycle and may enter a persistent anovulatory state, known as estropause [63]. this reinforces the idea that the ovarian reserve in mice, as in humans, is depleted with age and this process is completed in first half of the lifespan [60, 61]. the loss of ovarian function and the resulting decline in circulating estrogen levels are associated to various metabolic changes during induced menopause in rodents, similar to observed in women during natural menopause, such as increased adiposity, changes in lipid metabolism, hypertension, and insulin resistance [64, 65]. although mice do not naturally enter in menopause, it can be induced chemically or by ovariectomy. chemical menopause induction can be achieved by treatment with 4 vinylcyclohexene diepoxide (vcd). treatment with vcd causes atresia of primordial and primary follicles leading to exhaustion of the ovarian reserve but retention of ovarian tissue [66]. one study showed that as young as 6 month old rats induced to menopause by ovariectomy have a slight increase in systolic blood pressure (sbp), body weight, insulin resistance, and plasma cholesterol compared to intact females of the same age. this reinforces the notion that metabolic changes are driven by ovarian function independent of age [64]. these metabolic changes observed in ovariectomized rodents are a consequence of the hypoestrogenic state, similar to observed in women [65]. as estradiol reduction is one of the main effects of menopause, several studies have evaluated the benefits of exogenous estradiol replacement. studies in murine models point to some beneficial effects of estradiol replacement therapy. these effects include improvement of glucose homeostasis and insulin sensitivity [67], improvement of the innate immune response [68], and reduced arterial pressure [69]. interestingly, the transplantation of young ovaries into older females can increase lifespan [70], suggesting a protective effect of the ovarian tissue itself. transplantation of young ovarian tissue to post reproductive mice was able to significantly restore the cardioprotective benefits, similarly to what is seen at reproductive age [71]. these protective effects of ovarian tissue transplantation were also observed even when the young ovaries were follicle depleted with vcd prior to transplantation [72], suggesting that other factors beyond estrogen levels may play a role. therefore, novel therapies to replace estrogen could be developed, improving quality of life without side effects of hormone replacement therapies. faced with the hormonal and physiological changes induced by menopause, some alternatives also aim at delaying the onset of menopause in preclinical models, such as ovarian transplantation of young mice into old mice [70, 72], dietary strategies [61, 73], and use of drugs, such as rapamycin [74, 75] and metformin [76, 77] have been developed. dietary strategies have been proved widely effective in preserving the decline of follicle reserve in mice with aging. caloric restriction (cr), ranging from 10 to 30% reduction of calorie intake [78], is an intervention that has been proven efficient in promoting overall longevity [79] as well as extended fertility in females, due to its impact on the control of oxidative stress, insulin resistance, and reduction of the inflammatory state [80, 81]. cr can extend fertility by preserving the ovarian reserve [78, 82], reducing mtor and foxo3 activation [77, 83, 84], the main regulators of primordial follicle activation [83]. mice under 30% cr can still reproduce successfully around 15 16 months of age, when ad libitum fed mice could not [61]. in addition, cr also regulated dna repair mechanisms, preventing the accumulation of dna damage [85, 86], which could impact oocyte quality. however, some studies have associated the positive effects of cr to the restriction of protein [87]. protein restriction also results in lower activity of the mtor pathway in the ovary, decreasing the activation of primordial follicles and preserving the ovarian reserve [88]. the reduction in protein supply also results in lower adiposity and greater insulin sensitivity in humans and rodents, similar to that observed with 30% cr [87, 89]. on the other hand, hypercaloric diets (high fat and/or high carbohydrate diets) cause harmful metabolic adaptions, decreasing the ovarian reserve. mice exposed to a high fat diet have decreased ovarian reserve and increased insulin resistance and inflammation in the ovarian tissues [90, 91]. interestingly, this unhealthy diet decreased ovarian reserve even in the absence of body weight gain [90]. interestingly, the nematode c. elegans and the fly d. melanogaster can also serve as model for reproductive aging. c. elegans also have decreased reproductive potential as they age in both self fertile and mated reproduction [92]. as reviewed elsewhere, cr, metformin, and rapamycin treatment can also extend reproductive lifespan in c. elegans [92], resembling the effects observed in mice. similarly to the observed in humans and mice, an hyperactive germline in c. elegans is linked to reduced lifespan [93], suggesting a central role for reproductive fitness to regulate overall lifespan. the female fly d. melanogaster also has decreased reproductive potential with age [94]. in the fly, lifetime egg production was maximized in a diet containing a low protein to carbohydrate content [95]. the overall dietary restriction and rapamycin treatment both reduce daily egg laying, however increasing overall lifespan [96], further confirm a link between reproduction and lifespan in this species. based on ovarian physiology, animal studies, lessons from menopause and reproductive medicine studies, and the ideal strategy for delaying ovarian aging should have the following characteristics: (1) be initiated in the presence of good ovarian reserve; (2) maintained for a long period; (3) have an action on the dynamics of primordial follicles, controlling the rate of activation and atresia; and (4) safe use in pre conception, pregnancy, and lactation. recently, kulkarni et al. suggested the off label use of fda approved drugs to target aging [97]. based on animal and human studies that evaluated the effect of drugs on hallmarks of aging, healthspan, and lifespan, the authors scored (from 0 to 12) nine drugs according to potential anti aging effects. sodium glucose linked transporter 2 (sglt 2) inhibitors was the drug with the highest antiaging potential (score 12), followed by metformin (score 11), acarbose (score 9), rapamycin (score 9), methylene blue (score 9), angiotensin converting enzyme inhibitors and angiotensin receptor blockers (acei/arb) (score 8), dasatinib (+ quercetin) (score 6), aspirin (score 6), and n acetyl cyeteine (nac) (score 5) [97]. these nine potential anti aging drugs belong to different classes. three of these nine drugs are oral hypoglycemic agents, the sglt 2 inhibitors, metformin, and acarbose [97]. the impact of these gerotherapeutic agents on ovarian physiology is poorly understood. the benefit of using these hypoglycemic agents for female fertility is essentially due to adequate glycemic control and weight loss, with improvement in the ovulatory function [98]. however, the medium  and long term effects on ovarian aging are not well known. the effects of metformin on female reproductive outcomes are extensively studied, especially in patients with polycystic ovary syndrome. in addition to improving spontaneous pregnancy rates, increase implantation rates in ivf cycles, and decrease miscarriage rates among pcos patients, metformin regulates ovarian mechanisms that may contribute to a delay in ovarian aging [98]. studies in animal models have revealed that metformin reduces follicular atresia, oxidative stress, and autophagy in granulosa cells via the pi3k/akt/mtor pathway [99, 100]. qin et al. suggested that metformin may delay the ovarian aging process, probably by inducing sirt1 expression and reducing oxidative damage [76]. recently, landry et al. observed that metformin was able to prevent age associated ovarian fibrosis by modulating the proportion of fibroblasts, myofibroblasts, and immune cells [101]. at a dosage of 100 mg/kg, metformin was able to prevent the decline in the ovarian reserve with age in older mice [76]. in addition, metformin has chemoprotective effects in the ovaries of young mice exposed to cyclophosphamide [102]. therefore, metformin due improvement of insulin sensitivity has similar effects to a 30% cr diet, and can be an alternative to dietary interventions. rapamycin is a substance originally produced by the bacterium streptomyces hygroscopicus. in the past, rapamycin was used as an antifungal drug, later as an immunosuppressive agent [103]. rapamycin acts in tissues by inhibiting to mammalian target of rapamycin (mtor), a member of the phosphatidylinositol 3 kinase family of protein kinases. in this sense, mtor is a serine/threonine protein kinase that functions as a master regulator of cell growth and metabolism in response to nutritional and hormonal stimuli [104], and is suggested as a cr mimetic. the mtor signaling is involved in follicular dynamics, and its activation in granulosa cells promotes follicular development [105], and its inhibition can prolong ovarian lifespan [103]. animal studies have shown that treatment of female mice with rapamycin prevented activation of primordial follicles when compared to untreated controls [82, 106, 107]. our previous study suggested that treatment with rapamycin (4 mg/kg) prevents the decline in the ovarian reserve of mice similarly to 30% cr [82]. additionally, rapamycin administered to young animals (5 mg/kg) exposed to chemotherapy also decreased the activation of the mtor pathway, preserving the ovarian reserve [108]. among many adaptations with aging, there is an accumulation of senescent cells with age in several species [6, 109]. senescent cells have decreased capacity for proliferation [110 112], however remain metabolically active, secreting pro inflammatory factors known as senescence associated secretory phenotype (sasp) [113]. our group demonstrated an accumulation of senescent cells with aging also in the ovary of mice [62]. furthermore, we demonstrated that obese mice accumulate more senescent cells in the ovary than normal littermates [114], suggesting that obesity accelerates the ovarian aging phenotype. interestingly, senolytic drugs, such as dasatinib and quercetin (d + q), were able to reduce cellular senescence in the ovary of obese mice, without affecting the ovarian reserve. [114]. in young ovaries exposed to chemotherapy, an increase in cellular senescence was also observed, which was prevented by treatment with d + q [115]. furthermore, metformin along with d + q was able to reduce ovarian senescence even more, maintain regular estrous cycle, and prevent excessive primordial follicle activation [116]. nac is a stable form of the essential amino acid l cysteine. nac is converted to l cysteine after ingestion and subsequently converted to glutathione [117]. nac has important antioxidant and anti inflammatory properties [117]. animal studies have observed that nac is able to reduce ovarian damage by upregulating local antioxidant capacity and reducing ovarian secretion of pro inflammatory cytokines [118, 119]. in humans, the antioxidant action of nac contributed to reduce cell damage in ovarian tissue cryopreservation protocols [120, 121]. nac also has an antifibrotic action, already described in tissues such as muscle, aorta, and kidney [122 124]. therefore, although there are no studies evaluating the long term effect of nac on ovarian physiology, these properties may contribute to delaying ovarian aging. there are no animal or human studies evaluating a possible impact of sglt 2 inhibitors, acarbose, methylene blue, acei/arb, and aspirin on ovarian aging. we found no clear evidence in the literature that these intervention strategies can have a negative impact on overall fertility in animal models and humans. however, it should be noted that interventions that prevent ovarian aging result in retention of follicles in the primordial stage, which will have a negative effect on fertility during the period of the intervention. for example, in mice under 30% cr, follicles progress slower to secondary and tertiary stages, and, therefore, we observe a preserved pool of primordial follicles [82], which is desirable in the long term. however, as these follicles are not progressing to the secondary and tertiary stages, we observe a reduction in ovulation rate, reflecting in decreased fertility during the course of cr [78]. however, once mice are put back in ad libitum, feeding pregnancy rate increases [78] and is maintained above control group in aged mice due to preserved ovarian reserve [61]. therefore, in a proposed dietary/pharmacological intervention protocol to preserve the ovarian reserve, one should consider removing the treatment once pregnancy is desired. however, more studies are necessary to understand how long these interventions should be applied and how long before pregnancy is desired they should be interrupted, in order to maximize preservation of the ovarian reserve without compromising fertility. recently, numerous studies, including those by johnson et al. and white et al., have described the presence of ovarian germline stem cells (gscs) in ovaries of non mammals, mammals, and humans [125 128]. these findings began to question the dogma, established by zuckerman in 1951, of the inability of new ovarian germ cells to arise [129]. currently, studies seek to define protocols for ovarian rejuvenation or ovarian regeneration, through interventions that stimulate the emergence of new follicular units from gscs. injection of platelet rich plasma (prp) and stem cells into the ovaries are the two most studied treatments at present, especially in patients suffering from ovarian insufficiency and low ovarian reserve or undergoing ivf treatments with a poor prognosis [130 132]. in 2018, sills et al. were the first to describe that intraovarian injection of autologous prp significantly improved the response of four patients with diminished ovarian reserve as determined by at least one prior ivf cycle canceled for poor follicular recruitment response. decreased fsh and increased amh levels were also observed after the intervention. all four patients had at least 1 day five blastocyst available for cryopreservation [130]. currently, numerous studies are being conducted to validate the use of prp as an alternative treatment for female infertility associated with low ovarian reserve [133, 134]. intraovarian injection of mesenchymal stem cells (mscs) is another promising alternative to stimulate ovarian rejuvenation. mscs can originate from several sources, such as amniotic fluid, endometrium, germ cells, skin, umbilical cord, bone marrow, and adipose tissue [131]. stimulation of angiogenesis and cell proliferation, a decrease of apoptosis, modulation of immune cells function, and regulation of gene expression in the ovary are possible mechanisms involved in the process of ovarian rejuvenation that are observed after msc transplantation [131]. however, clinical studies are needed to evaluate the impact of treating women with low ovarian reserve undergoing ivf cycles. based on the evidence presented in this review, it becomes clear that the ovarian reserve has a central role in the female life. the progressive decline in the ovarian reserve with age is natural; however, it can be accelerated by several factors, like diet and lifestyle. once the ovarian reserve starts to become severely compromised, females experience a decline in natural fertility, as well as in the response to assisted reproductive technologies. later in life, once this ovarian reserve is depleted, females experience changes in the body physiology, resulting in increased chronic disease and mortality risk. therefore, the use of strategies to prevent the decline in the ovarian reserve should be investigated to improve fertility, healthspan, and lifespan. there are several drugs that can be repurposed for this aim; however, we need to better understand the best moment that these therapies must be initiated to promote the desired effects (fig. 1). ovarian aging results from activation of primordial follicles. this decline in the ovarian reserve leads to reduce fertility and menopause later in the female life. despite some lifestyle factors are a risk for decreased ovarian reserve, some strategies can prevent this decline funcap ps1 0186 00240.01.00/21; unifor 60/2022; capes; cnpq; fapergs; nih/nia r56ag074499. the authors declare no competing interests. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. articles from geroscience are provided here courtesy of springer connect with nlm national library of medicine 8600 rockville pike bethesda, md 20894

an official website of the united states government official websites use .gov a .gov website belongs to an official government organization in the united states. secure .gov websites use https a lock ( lock locked padlock icon ) or https:// means you've safely connected to the .gov website. share sensitive information only on official, secure websites. primary site navigation logged in as: correspondence to: shixuan wang; email: sxwang@tjh.tjmu.edu.cn corresponding author. received 2018 nov 12; accepted 2019 jan 15; collection date 2019 jan 31. this is an open access article distributed under the terms of the creative commons attribution (cc by) 3.0 license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. aging has been regarded as a treatable condition, and delaying aging could prevent some diseases. ovarian aging, a special type of organ senescence, is the earliest aging organ, as ovaries exhibit an accelerated rate of aging with characteristics of gradual declines in ovarian follicle quantity and quality since birth, compared to other organs. ovarian aging is considered as the pacemaker of female body aging, which drives the aging of multiple organs of the body. hence, anti ovarian aging has become a research topic broadly interesting to both biomedical scientists and pharmaceutical industry. a marked progress has been made in exploration of possible anti ovarian agents or approaches, such as calorie restriction mimetics, antioxidants, autophagy inducers etc., over the past years. this review is attempted to discuss recent advances in the area of anti ovarian aging pharmacology and to offer new insights into our better understanding of molecular mechanisms underlying ovarian aging, which might be informative for future prevention and treatment of ovarian aging and its related diseases. keywords: organ senescence, ovarian aging, pacemaker, pharmacological strategies as human longevity has been significantly improved, aging related problems are markedly increasing. it is predicted that the number of people over 60 years old by 2050 will be five times than that of 1950 [1]. as the world's most populous country, china entered into the aging society 13 years ago. according to the previous population census data, the aged population in china has exceeded world average in size, growth rate and proportion. the average lifespan of chinese people will increase to 81.9 by 2040 [2]. the primary problem of the aging population is the serious detriments caused by the aging of various organs and the decline of their functions. organ senescence is often highly associated with a variety of diseases, such as cancer, diabetes, cardiovascular disease and obesity. the occurrence and development of these diseases lead to the decrease of the life quality and increase of the proportion of people who live with the diseases. however, fortunately, aging has been shown to be an improvable condition, and delaying aging would be a way to prevent and treat diseases [3]. one of the earlier aging organs is ovary, as it exhibits an accelerated rate of aging compared with that of other body systems. ovarian aging is characterized by gradual declines in ovarian follicle quantity and quality, ending with menopause [4]. the ovarian aging process is complicated and affected by a number of factors, including lifestyle, medical, genetic, autoimmune, environmental, and idiopathic ones. thus, ovarian aging can be physiologic ovarian aging, which is defined by age specific declines of functional ovarian reserve, and also premature ovarian failure (pof) due to those aforementioned factors. for women, anti mullerian hormone (amh )and antral follicle counts (afc) are currently best markers for evaluating ovarian reserve. in addition, age and menstrual cycle are also good indicators. for animals, ovarian reserve is often reflected in follicle counts at all stages. endocrine function is mainly reflected by hormone levels and estrous cycle regularity. reproductive ability includes pregnant rate, litter size, number of offspring per litter, and so on. ovarian aging is a complex process. since birth, a large number of follicles in the ovaries have undergone atresia during development. a woman only ovulates about 500 times in her lifetime, and 99% of the follicles are wasted. rapid deterioration in both the ovarian follicle quality and quantity is highly associated with a number of women’ disorders or diseases. the fertility of women decreases gradually with age, and after age 35, it declines more rapidly until menopause at an average age of 51 [5]. currently, more than 15% of couples in the world face the problem of infertility in their childbearing years, which is expected to reach 7 million by 2025 [6]. what’s more, estrogen secretion decreases with the decline of ovarian function and the arrival of menopause, which then lead to multiple organ dysfunction, such as heart disease, osteoporosis, cancer, obesity, senile dementia, and so on [7]. the incidence rate of osteoporotic fractures in postmenopausal women is significantly higher than that before menopause, and the risk index is much higher than that of men of the same age. in addition, cardiovascular diseases are often called "gender difference" diseases, because of their dramatic increase in postmenopausal women [8 10]. thus, ovarian aging is considered as the pacemaker of female body aging, which drives the aging of multiple organs of the body [11]. hence, it becomes particularly important to study molecular events underlying this fast aging process, as doing so would help us not only better understand this process, but also develop possible strategies or approaches to slow it down for hopefully preventing ovary aging associated diseases. the past decade has witnessed a great progress in this area. this review is aimed to discuss recent advances in the pharmacological research toward development of anti ovarian aging agents or approaches and to offer some insights into our better understanding of the ovary aging process and its molecular events. we hope that this review with a broad collection of literature would be informative and useful to ovary researchers and others who are interested in this topic. the subtitles and classifications in this article referred to one published article regarding anti aging pharmacological strategies [12]. the free radical theory of aging has been a classical and the most influential theory in the field of aging, since was first postulated by denham harman in the middle of the last century. oxidative stress leads to changes in the ovarian microenvironment, and these changes account for ovarian senescence and the decrease of ovarian reserve [13, 14]. during the senescence process, the level of reactive oxygen species (ros) increases, while the expression and activity of oxidative defense system related enzymes are significantly reduced. these all lead to a wide range of oxidative damage, including the cell membrane lipid peroxidation, protein oxidation and enzymes inactivation and dna damage [15 21]. also, ros in follicle oocytes, corpus luteum cells and follicular fluid of elderly women who receive assisted reproductive technology (art) increases significantly, while antioxidant enzymes decreased; this causes the low success rate of art [22 24]. it has been shown that oxidative damage products of dna, protein and lipid in ovarian stromal cells increase markedly with age [25]. clinical studies have also shown that higher ros levels exist in unfertilized eggs or low quality embryos [23, 26]. all these studies indicate that oxidative stress plays an important role in ovarian aging. therefore, antioxidants have been used to prevent ovarian aging among all of the currently used antioxidants, vitamins c and e are commonly used as natural antioxidants. they are also the most studied ones. vitamin c is the major water soluble antioxidant, which can effectively reduce a tocopheroxyl radicals and level of low density lipoprotein (ldl) in cell membranes, thereby restoring a tocopherol and inhibiting the generation of free radicals [27]. vitamin e is the main hydrophobic antioxidant protecting cell membranes from oxidative damage by reaction with lipid radicals produced in the course of the lipid peroxidation chain reaction. the dietary vitamin e supplementation has been shown to be associated with reduced risk of atherosclerosis by reducing oxidative stress and inhibiting ldl oxidation [28]. these cellular studies are supported by an animal study, as oral administration of vitamins c and e could prevent the aging‐related negative effects on ovarian reserve (number of ovarian oocytes and number of ovulated oocytes) and oocyte quality (chromosomal aberration in metaphase ii oocytes and morphological apoptotic oocytes) in mice [29]. therefore, vitamins c and e can be useful for preventing ovary aging. there are several lines of increasing evidence for benefits of using the antioxidant n acetyl l cysteine (nac) in preventing ros induced damage and pathology. previous studies have shown that nac effectively reduces oxidative stress induced telomere shortening, telomere fusion and chromosomal instability in oocytes in vitro, and improves oocyte and early embryo development [30 32]. another study using nac in drinking water for mice for two months showed that nac can improve the quality of mouse oocytes and promote the early embryonic development. by offering 1 to 1.5 months old mice with low doses of nac for one year, this lab also found that nac increases the litter size and oocyte quality of 7 to 10 months old mice and also telomerase activity and telomerase length [33]. these studies indicate that appropriate treatment with the antioxidants, such as vitamins c, vitamins e or nac, can postpone ovarian aging by reducing free radicals. curcumin is an active ingredient extracted from the dietary spice turmeric and has been utilized for medicinal purposes for thousands of years. the activity of curcumin as an antioxidant and free radical scavenger has been demonstrated by several studies [34]. recently, more studies have demonstrated that curcumin could protect ovarian reserve and ovarian function from tissue injuries. curcumin might be a promising treatment for cyclophosphamide induced pof, because of its improvements in ovarian tissue histopathological damage, hormonal levels and reduced oxidative damages. it decreased vascular congestion and atretic follicles, increased healthy follicles numbers, and enhanced the levels of malondialdehyde (mda), glutathione (gsh), superoxide dismutase (sod), glutathione peroxidase (gpx), and catalase (cat) in rat ovarian tissue [35]. in an ischemia reperfusion rat model, curcumin could maintain and protect ovarian functions from oxidative injury [36]. another study also indicated that curcumin can alleviate sodium arsenite induced ovarian oxidative injury in a mouse model to a certain extent by increasing the levels of sod and decreasing ros and mda expression [37]. curcumin combined with flutamide could modulate ovarian structure and abdominal obesity in aging fsh r haploinsufficient mice. in this model, curcumin enhanced the expression of bone morphogenetic protein 15 in the ovary and improved structural changes of in zona pellucida [38]. these studies indicate the beneficial outcomes of curcumin treatment in ovarian reserve and function protection. coenzyme q10 (coq10), an oil soluble component of nearly all cell membranes, acts as an antioxidant in cellular metabolism via inhibition of lipid peroxidation, protein, and dna oxidation [39,40]. coq10 is an essential component for transporting electrons in the mitochondrial respiratory chain to produce cellular energy. studies have shown that supplementation of coq10 protects cells from ros induced damage due to its antioxidant properties, which strengthen endogenous cellular antioxidant systems. coq10 also restores oocyte mitochondrial function and fertility during reproductive aging. thus, dietary administration of coq10 could prevent age related decline in oocyte quality and quantity, and oocyte specific pdss2 deficient induced diminished ovarian reserve [41]. another study indicate that coq10 supplementation may protect ovarian reserve by counteracting ovarian aging induced by either mal functional mitochondria or physiological programming, and reducing the expression of 8’ohdg [42]. coq10 may restore ovarian function and reserve of aging mice, and more researches are needed to verify its effects. proanthocyanidin is a phenolic compound exists in fruits, vegetables, nuts, seeds, wines and tea, which has been indicated to be effective in protecting tissues from oxidative damage [43]. researchers have found that proanthocyanidin extracted from grape seed could maintain the homeostasis between cell proliferation and apoptosis, reduce oxidative damage in the d gal induced and natural aging ovaries, and alleviate d gal induced nucleus chromatin condensation, thus effectively delay the ovarian aging process in hens [44]. currently, grape seeds have been widely produced as an antioxidant supplement and used for healthy living. more clinical trials are expected to demonstrate the role of proanthocyanidin in protecting ovarian function and delaying ovarian aging process in the human. some plant polyphenols can also protect ovarian reserve and ovarian function by acting as antioxidants. quercetin is a potential antioxidant and free radical scavenger that is widely found in fruits, vegetables, and leaves. quercetin increases the antioxidant capacity of the ovary in menopausal rats and in ovarian granulosa cell culture in vitro by upregulating the expression of some oxidative stress related genes, such as sod 1, cat and glutathione synthetase (gss) [45]. some research suggested that tea polyphenols may inhibit the transition from primordial to developing follicles, extend the entire growth phase of a follicle and reduce dominant follicle numbers per cycle. thus, tea polyphenols increased the reserve of germ cells, inhibited oocyte apoptosis and follicle atresia during ovarian development from birth to early aged, and retard climacterium in rats [46]. drinking even a small cup of tea per day may extent the productive life of ovary. hence, these studies indicate that antioxidants can prevent ovarian aging and enhance ovary function by either activating the expression of genes important for reduction of oxidative damages or directly scavenging or inactivating ros. over the past years, it has been shown that improvement of cellular and physiological metabolisms could also prevent ovarian aging. one of the approaches is caloric restriction (cr), also known as dietary restriction (dr). cr by limiting the daily diet to 25%   50% of the normal diet ensures that the body receives sufficient nutrients without malnutrition. the ability of cr to extend lifespan and delay aging have drawn noteworthy researchers’ attention since the original work was reported by mccay and colleagues eighty years ago [47]. since then, a number of studies have confirmed that cr is the most effective means to postpone the aging of the body and extend lifespan of many organisms. thereby it is the most inspiring discovery in the aging field [48]. cr can not only prolong the average life expectancy of rodents, but also improve the fertility and prolong the reproductive life [49], by delaying the process of ovarian aging. although cr is so effective, its implementation is not so easy in real life practice. thus, alternative substances have been looked for to mimic the cr effects as further detailed below. also, the main signaling pathways that mediate the cr effects and the most promising pharmacological substances that modulate these pathways and mimic the cr effects will be discussed in the following sections. since cr can reduce the levels of insulin, blood glucose, and increase insulin sensitivity [50], inhibitors of the enzymes involved in the process of saccharide decomposition has been searched to simulate the cr like effect on delaying aging [51]. one of the main inhibitors of this kind is metformin that has been used for the treatment of type 2 diabetes. metformin has been shown to effectively improve the symptoms, such as insulin resistance, hyperinsulinemia, blood lipid metabolism. it can also prevent diabetes induced large blood vessels and pathological changes of capillaries, and then reverse early diabetes. metformin may also act as a cr mimetic since it can decrease the production of hepatic glucose, by inhibiting of the mitochondrial respiratory  chain complex 1 [52]. recently, metformin has become a hot research topic in the field of aging. in 2015, metformin was proposed for trials in delaying human aging [3]. the current studies of metformin in ovaries are mainly limited to polycystic ovary syndrome (pcos) and ovarian cancer. several studies have shown that metformin can improve ovarian function in patients with pcos [52]. it could directly affect ovarian theca cells and decreased fsh stimulated 3β hsd, star, cyp11a1 and aromatase activities in both rat granulosa cells and women with pcos, with reduction of basal and of fsh stimulated progesterone and estradiol levels as a consequence [53]. however, results from another study showed that metformin has no significant effect on ovarian reserve [54]. thus, the specific effect of metformin on ovarian reserve and function in normal animals or women needs a more systematic investigation. previous studies have indicated that insulin like growth factor i (igf 1) and its binding protein igfbp 1 in follicular fluid may reflect ovarian reserve [55]. one small molecule inhibitor in metabolic enzymes, which might have a cr like effect on ovarian aging is the synthetic glucose analog 2 deoxy glucose (2 dg). several studies have shown the activity and mechanisms of action of 2 dg for treating viral infection, epilepsy and cancer [56,57]. in mice, 2 dg treatment induced foxo3 activity and inhibited primordial follicle activation, suggesting that 2 dg may be useful for fertility preservation [58]. besides 2 dg, tamoxifen, an inhibitor of estrogen receptor (er) often used for treatment of er positive breast and ovarian cancers [59,60] has also been shown to be potentially useful for improving ovarian aging. it was shown to regulate the iis signaling involved in the occurrence of ovarian aging, and to keep the level of igf 1 in the ovary [61]. an animal study also showed that tamoxifen can promote follicular development and amh expression of and protect ovarian functions and the fertility of radiotherapy rats by enhancing the expression level of igf 1 in ovaries [62]. finally, regulation of the mammalian target of rapamycin protein (mtor) has been shown to effectively simulate cr effects, extend lifespan, and delay aging [63]. as a serine/threonine protein kinase, mtor regulates cell growth, proliferation, differentiation and the cell cycle [64]. recent studies have shown that mtor related signaling pathways play an important role in aging associated metabolic diseases, such as obesity, type 2 diabetes and cancer [65]. inhibiting the mtor pathway can extend the life span of several species, such as worms [66,67], fruit flies [68] and mice [69]. analysis of gene expression profiles indicated that the mtor pathway is closely related to human health and life span [70]. recently, rapamycin, an inhibitor of mtor and a new type of macrolide immunosuppressant, has also been shown to inhibit the activation of the initial follicle by regulating the mtor and sirtuin signaling pathways, thus protecting ovarian reserve and extending the reproductive life of the ovary [71 73]. rapamycin may provide a new strategy for patients with premature ovarian failure by protecting ovarian reserve in the near future. over the past few years, a series of epigenetic regulators have been identified, such as small molecule inhibitors of dna methylation and histone acetyltransferases or non coding rnas. these regulators have the potency of treating cancer, myelodysplastic syndrome and neural degeneration [74]. epigenetic regulations are involved in the changes of gene or protein expressions without altering dna sequence. epigenetic modifications are reversible. this characteristic makes small molecule epigenetic regulators attractive as aging intervention agents [75]. in the past 20 years, the role of histone and genomic epigenetic modification regulation in ovarian aging has been gradually recognized, and has become a research hotspot in this field. abnormal regulation of the related gene expression can lead to ovarian cell apoptosis and accelerated aging, which in turn can accelerate the aging of the ovaries [76]. although little is known about the role of small molecule regulators of dna methylases and histone acetyltransferases in ovarian senescence, there are a few studies that suggest that some of them might be useful for improvement of ovarian aging. for example, the sirtuin deacetylase family with seven members in mammalian cells plays a very important role in cell survival, apoptosis, aging, and may be one of the common life span control family genes in eukaryotic organisms. it was shown that a sirt1 activator can increase ovarian reserve and prolong reproductive life of obese mice induced by high fat diet by activating sirt1 and inhibiting mtor signaling pathway [77]. also, resveratrol have been reported to protect mice from aging associated infertility by activating sirt1 gene expression, improving the number and quality of oocytes, as shown by spindle morphology and chromosome alignment [78]. resveratrol could improve the rat ovarian reserve and prolong the reproductive life, which may be due to inhibition of the activation of primordial follicle pool and follicular atresia [79]. these studies suggest that targeting epigenetic molecules might serve as an effective approach to improve ovary functions and to delay ovarian aging, though much more need to be done. microrna profile changes in the ovaries of dwarf mice during the aging process, which suggests that these mirnas may play vital roles in maintaining younger of ovarian phenotype [80]. another study suggests that specific non coding rnas profiles are associated with age and ovarian reserve, indicating that oocyte quality might be mediated by ncrna pathways [81]. however, there are no pharmacological strategies targeted at micrornas to improve ovarian reserve or delaying ovarian aging process recently. autophagy is an intracellular bulk degradation system. during the process, part of the cytoplasm is enveloped in the autophagosomes, then fused and degraded by lysosomes [82]. several clinical trials are exploring autophagy as a therapeutic target as it plays vital roles in age associated diseases [83]. in the ovaries, germ cell death is triggered by autophagy or apoptosis during the establishment of ovarian reserve [84]. studies also suggest that autophagy may promote the formation of the primordial follicle pool [85], which also regulates ovarian follicle atresia [86]. however, few drugs delayed ovarian aging process by targeting autophagy signal pathway. melatonin and resveratrol are potential autophagy inducers that may extend ovarian lifespan. melatonin is of quite capacity to delay ovarian aging for its regulation of multiple pathways such as oxidative stress, telomeres length and sirts, in which autophagy plays a vital role [87 89]. furthermore, resveratrol improved the quality of oocytes by inducing autophagy and mitochondrial synthesis in aged cows [90]. the role of autophagy in ovarian aging process needs more research, and drugs target at autophagy should be explored later. studies have indicated that telomere length are strongly associated with lifespan [91]. reports on the role of the telomere and telomerase in female ovaries are still limited. positive correlations were found between female reproductive life span, being widely accepted as ovarian reserve, and the telomere length [92]. the telomere length, serving as a biological clock, may play vital roles in limited ovarian lifespan, particularly at the cellular level [93]. another study suggests that telomere length and telomerase activity are associated with primary ovarian insufficiency, which may indicate the progression of ovarian decline [94]. compared to oocytes from young females, telomere length from the aged was remarkably shorter [95]. we have mentioned above that nac could delay the oocyte aging by antioxidant activity. the telomerase activity and telomere length were also increased in the ovaries of mice treated with nac [33]. another study found that resveratrol protects against age associated infertility in mice by enhancing telomerase activity and increasing telomere length in the ovaries [96]. these studies suggest that telomerase activators may extend ovarian lifespan effectively. melatonin is a natural amine hormone secreted principally by pineal gland and released into circulation in a pulsatile fashion with the sharpest peaks in the early morning [97]. light inhibits the secretion of melatonin and changes the time phase of melatonin rhythm. different from the aforementioned antioxidants, melatonin possesses a variety of activities in the metabolic and physiological process. melatonin exhibits direct free radical scavenging and indirect antioxidant effects. the main mechanism by which melatonin protects cell structure is to eliminate free radicals, inhibit the lipid peroxidation reaction and regulate activity of antioxidant and pro oxidant enzymes. these actions of melatonin are believed to be mediated by the keap1 nrf2 are pathway and activation of sirtuin 1 (sirt1). the role of melatonin in preventing ovarian aging has been also reported. previous studies have shown that shortening the time of sunshine can delay reproductive aging [98,99]. researchers gave 10 day old mice lifetime doses of melatonin and found that it delayed puberty arriving and the aging of the reproductive system, but had no effect on the size of the primordial follicle pool [100]. another study showed that orally giving kunming mice at 2 3 months old age with melatonin for 12 months can significantly delay ovarian aging by increasing the total number of follicles and the number and quality of oocyte in mice, extending the telomere length, improving the fertility of old mice and reducing the ovaries the generation of ros [101]. melatonin treatment for 2 months can increase ovarian volume, improve estrous cycle, and maintain estrogen secretion of 13 month old rat (middle aged) significantly, maintaining their hormone levels equivalent to that of young rats [102]. this study also showed that melatonin can extend the reproductive lifespan of the middle aged and old rats. in a clinical study, perimenopausal and postmenopausal women of 42 62 years old were given melatonin treatment for six months. amazingly, after the treatment, 43 49 years old women have significantly higher serum levels of lh, and their pituitary and thyroid function normally [103]. finally, recent studies showed that melatonin can increase the primordial follicle pool size, delay ovarian aging in mice by enhancing antioxidant capacity, maintaining the telomerase activity, stimulating the sirt1 expression and the ribosomal function [104]. these phenomena indicate that melatonin might promote the recovery of ovarian cycle and improve the elderly female fertility. hormones have been shown to play a role in ovarian ageing as well. for example, leptin has been demonstrated to be essential for ovarian follicle development and fertility. the expression of the leptin receptor in ovary is regulated throughout the estrous cycle by ovarian steroids, with peak expression at ovulation, indicating a possible involvement of this hormone in follicular development and corpus luteum formation. also, igf i plays an important role in leptin receptor expression during the entire estrous cycle, especially during the prepubertal period [105]. during superovulation, leptin administration with gonadotropins in aged mice increased the ovarian response, developmental competence of oocytes and ovarian vegf expression [106]. it was also shown that leptin causes an inhibitory effect on the early follicular development in both immature and adult mice, although the underlying inhibitory mechanisms of leptin may be different [107]. another study indicated that reduction of peripheral leptin in the circulation promotes ovarian follicle development in prepubertal female mice, suggesting that leptin acts as an inhibitor of ovarian follicle development [108]. leptin deficiency in mice was associated with impaired folliculogenesis, which resulted in increased follicular atresia. thereby, leptin deficiency induced follicle impairment may be one of the causative factor of infertility [109]. the recent study showed that neonatal overfeeding induces early decline of the ovarian reserve, and acute effects of elevated circulating leptin may be responsible for the long term reproductive outcomes, thus leading to premature ovarian ageing and changes in reproductive efficiency [110]. dehydroepiandrosterone (dhea) is a hormone essential for human health, especially for women. all estrogens and nearly half of androgens are synthesized from dhea in peripheral tissues. more studies have shown that dhea can increase pregnancy rate, promote the steroid hormone secretion, increase the amh expression and the number of antral follicles, which may also be due to the increased expression level of the igf 1 [111]. recent study indicates that dhea supplementation prior to assisted reproductive technology (art) improves ovarian markers such as serum amh, inhibin b and antral follicle count (afc) in patients with diminished ovarian reserve [112,113]. dhea also has a pro inflammatory immune potential and regulates the balance of cd4+/cd8+ t cells. another study has also demonstrated that dhea supplementation improves the ovarian reserve of women with diminished ovarian reserve which may due to its regulation of the immune response in the ovaries [114]. in a cortical autograft experimental sheep model, dhea was applied for 10 weeks. the increased the expression of both the proliferation marker ki 67 in granulosa cells and the follicular amh expression at the preantral and early antral follicle stages was observed [115]. the results mentioned above suggest that dhea may delay ovarian aging. however, long term treatment with dhea may affect folliculogenesis and lead to follicular atresia through interaction with amh [116]. thus, the concentration and duration of dhea treatment is of great importance. growth hormone (gh) is a peptide which can promote cell proliferation and body development in animals and humans. gh has been applied to children and adults who suffers gh deficiency clinically. mice lack of gh receptor showed the reduction of primordial follicle pool and the decrease of their survival rate of growing follicles. results suggest that gh may be involved in the process of primordial follicle pool recruitment via the igf 1 pathway, and inhibition of apoptosis of follicles [117]. gh can protect ovarian function from radiation therapy damage, promote the follicular development,and improve amh expression by increasing igf 1expression and repressing radiation induced oxidative damage in ovary [118]. hormone replacement therapy (hrt) is a universal treatment for premature ovarian failure (pof), mainly including estrogen therapy, estrogen and progesterone sequential therapy. studies have shown that young pof patients treated with hormones show the development of secondary sex characters and alleviated perimenopausal syndrome [119]. estrogen therapy can promote the endometrial proliferation in pof patients, maintain the estradiol concentration in the blood circulation and promote the pregnancy of women [120]. estrogen and progesterone sequential therapy could enable pof patients to establish regular artificial cycles and improve pregnancy rate [121]. by comparing standard hrt treatment with percutaneous estrogen delivery combined with vaginal progesterone treatment, researchers found out that these treatments have similar effects on inhibition of fsh and lh, although the combination is more advantageous to cardiovascular protection [122]. hence hormones based treatments can be practically useful for improvement of ovary functions and delay of ovarian aging. a recent study suggested that progesterone alone may protect ovarian function from ischemia reperfusion injury through its anti apoptotic and antioxidative properties [123]. more researches are still needed for the role of progesterone in ovarian function. a variety of autoimmune antibodies, such as anti nuclear antibodies and anti ovarian tissue antibodies, have been found to be related to pof [124]. therefore, immunotherapy is of certain significance to patients with pof. in theory, immunomodulators are effective against autoimmune pof. it has been reported that patients treated with clinical immunosuppressive agents, such as glucocorticoid can resume ovulation and pregnancy, but the effect is not so clear. administration of the immunosuppressant diethyleneethanol and freund's adjuvant during prepubertal provided sufficient anti gnrh for calfs to delay the onset of puberty for 112 days [125]. treatment with corticosteroids and testosterone can significantly improve the general condition of pof mice models by reducing the levels of lymphocytes, immune globulins, and related antibodies [126]. however, the clinical application of glucocorticoid has many adverse reactions and the long term curative effect need to be followed up. it was shown that the effect of androgens on autoimmune pof is significant, and their side effects are relatively less significant, so the patient's compliance is better. androgens may inhibit the immune system by regulating the hypothalamic pituitary gonad axis [127]. since the optimal treatment time and duration of pof with glucocorticoid or androgen have not been determined, further studies are needed. traditional chinese medicine holds that symptoms of perimenopausal women are related to the imbalance in the body of yin and yang, disturbance of viscera. deficiency of the kidney energy is the fundamental cause, so it should be given priority to tonifying kidney and spleen, accompanied by protecting liver and calming nerves. some can achieve satisfactory curative effect, such as bushen huoxue recipe, liu wei di huang jia jian, zuo gui wan jia jian and so on. the mechanisms of traditional chinese medicine are complicated as the pharmacological ingredients are complex. recent years, several studies have found that traditional chinese medicine may regulate women nervous endocrine system and immune system by removing free radicals, improving ovarian microcirculation and reducing cell apoptosis, and then delay ovarian aging [128,129]. the experiments of animals have revealed that, with age, the levels of nerve growth factor and norepinephrine (ne) in the ovaries, and the increase of sympathetic nervous activity were related to reproductive ability of rats. electric acupuncture can promote the recovery of ovulation and increase fertility of older rats by reducing the level of ngf in ovary or blocking the activity of ne [130]. intragastric administration of american ginseng gavage can protect the rat ovaries from vcd induced pof, promote the prostaglandin synthesis and ovulation, reduce the serum levels of pge2, fsh and lh, remain the e2 to the normal level [131]. bushen huoxue recipe alleviates cyclophosphamide induced diminished ovarian reserve in mouse model by elevating the proportions of cd4+ t cells, th1, th17, treg subsets and increasing serum levels of ifn γ, tnf α, il 17a, il 6 and il 10 as well as the mrna expressions of t bet. these results show that bushen huoxue recipe is a promising candidate to treat diminished ovarian reserve mice and this beneficial effect may be mediated through the downregulation of augmented autoimmunity [132]. another study indicated that bushen huoxue recipe might improve the ovarian reserve and enhance the ovarian function of pof mice through neo oogenesis [133]. bushen tiaochong recipe might exert its beneficial role in oocyte maturation and restore diminished ovarian reserve through regulating the brain derived neurotrophic factor pathway [134]. yifuning, a traditional chinese medicine recipe, has been used for many years in china, for its effects on treating climacteric syndrome. studies suggest that it can improve the general condition of aging rats and mice, promote hormone secretion, recover estrous cycle, increase the viscera index of ovary and uterus and improve perimenopausal syndrome symptoms. it can also improve the function of natural aging reproductive organs such as ovary, uterus and vaginal, which may be related to its activities of antioxidant and promoting proliferation [135]. the bushen compound could delay the ovarian aging of rats and significantly improve their reproductive and endocrine functions by reducing oxidative damage, promoting the production of vegf, igf 1 growth factor, reducing the level of tnf α in the ovarian tissue, and effectively improving ovaries microenvironment. it can also improve the ultrastructure of ovarian tissue and enhance the immune function of the body [136]. diosgenin improves ovarian reserve in naturally aging mice by increasing the number of primary follicles and serum levels of amh. the mrna expression of nobox, gdf9 and bmp15 was also evaluated [137]. our recent study have also indicated that kuntai capsule may improve damaged ovarian function, which may be related to its antioxidant and anti apoptosis effects [138]. as the components of traditional chinese medicine are complex, they may have several pharmacological actions and work through a variety of pathways. traditional chinese medicine shows a great potential in delaying ovarian aging and extending ovarian lifespan. nowadays, many young women choose to delay or avoid marriage and/or giving a birth owing to the accelerated pace of our society and various pressures from work and family. however, their ovarian reserves strictly define their best age of fertility, since a sharp decline in ovarian functions is observed after age 35, which defines a high risk period. after 35 years old, the rate of pregnancy markedly decreases while miscarriage and premature birth for a woman increase significantly. consequently, the health of maternal females and child is threatened post this stage. therefore, more systematic and careful studies of the female reproductive system, especially the mechanisms of ovarian aging and the effective delay strategies, are of great importance. current research on ovarian aging mechanisms, such as primordial follicles activation and follicular atresia, have provided new insights into our better understanding of molecular mechanisms underlying ovarian aging delay. this rich information has been useful for development of anti ovarian aging therapies as described above. upon our review, some drugs may have several pharmacological actions and work through a variety of pathways (figure 1). we believe that, upon future establishments of effective therapies, it will no longer be a fantasy to extend women's reproductive life and delay menopause with the development of medical advances in this specific area. classification of anti ovarian aging drugs. some drugs may have several pharmacological actions. the important contributions of our graduate students and colleagues in this research are gratefully acknowledged. conflicts of interest: the authors have no conflicts of interest. funding: this research was supported by the grant from the key national research and development projects (2016yfc1302900) and national natural science foundation of china (no.81671394, no.81370469, no.81873824). articles from aging (albany ny) are provided here courtesy of impact journals, llc connect with nlm national library of medicine 8600 rockville pike bethesda, md 20894

thank you for visiting nature.com. you are using a browser version with limited support for css. to obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in internet explorer). in the meantime, to ensure continued support, we are displaying the site without styles and javascript. lynne peeples is a science journalist in seattle, washington. you can also search for this author in pubmed google scholar illustration: maria corte in late 2022, naomi busch, a lone physician in her book group, began fielding question after question about menopause. members of the group had started to experience the hallmark symptoms   hot flushes, poor sleep and mood swings   and wondered what they could do about them. “they all looked at me,” says busch, “and i was like, ‘i don’t know anything about menopause.’” she searched for knowledgeable physicians in and around seattle, where she lives, but the few specialists were booked out for several months. meanwhile, the women in the book group were not getting the answers that they needed from their gynaecologists or primary care physicians. “i’m not going down quietly,” busch remembers one woman vowing. busch, who trained in and practised primary care medicine, wasn’t surprised by the lack of information. “it’s not something we learn about in medical school,” she says. so busch decided to find out everything she could about menopause. ultimately, she passed a competency exam to become a certified practitioner through the menopause society, a non profit organization based in pepper pike, ohio, that provides tools and resources to health care professionals. she’s not alone in her interest. more than 1,300 providers became certified in 2024; and more than five times as many people applied for the exam in 2024 as in 2022. the international menopause society, a uk based charity, also offers a free online training programme for health care professionals. more than 2,600 people completed the course in 2024, up from under 2,000 in 2023. menopause research is globally underfunded. it’s time to change that menopause research is globally underfunded. it’s time to change that many health care professionals   along with society in general   regularly tell women, and transgender, non binary and intersex people who go through menopause, to accept the misery of the transition, and the health troubles that can follow. menopause comes with increased risks of health conditions such as cardiovascular disease, diabetes, osteoporosis and memory loss. yet, few medical options are typically presented to people going through menopause. sometimes, oral contraceptives are prescribed to ease symptoms and prevent unwanted pregnancies, which are still possible during the transition. but common doses and formulations can include risks, such as developing blood clots, and don’t always provide sufficient treatment, says busch. non hormonal drugs, such as fezolinetant and elinzanetant, treat hot flushes   but they also have side effects. other options include antidepressants, cognitive behavioural therapy, acupuncture and lifestyle changes, which usually go only so far in alleviating symptoms. hormone replacement therapy, which was a routine treatment until 2002, is widely passed over, owing to a misinterpreted study1 that prompted fear of its use. the outlook for managing menopause is now starting to change, say researchers and clinicians. treatments   both old and emerging   are offering hope. some researchers, for example, are revisiting hormone therapy and the optimal time for treatment to start. others are exploring the benefits of stalling the onset of menopause after decades of neglect, research funding for menopause, as well as public awareness, are now on the rise. this is a notable step in what advocates hope could be a revolution in women’s health. in may 2024, the us national institutes of health held a round table on future directions in menopause research, and through a white house initiative that year, the administration of then president joe biden awarded us$113 million to women’s health research. meanwhile, a groundswell of vocal advocates around the world continue to push for awareness of how menopause affects health. actor halle berry has joined us senators in championing a bill that would boost menopause research; a uk based group of women called menopause mandate has organized walks to raise awareness; and menopause solutions africa offers workplace training programmes. it’s hard to imagine a therapeutic space that would have as much potential payoff, specialists say. menopause affects half the population, and it interrupts a time when people are in their prime professionally. “there is renewed interest in menopause right now, and we need to take advantage,” says stephanie faubion, the director of mayo clinic’s center for women’s health in jacksonville, florida, and medical director of the menopause society. for decades, what researchers are now pushing to call ‘menopausal hormone therapy’ was the gold standard of care for alleviating common symptoms of the menopause transition. menopause occurs when the ovaries’ last eggs are depleted. practically, it’s defined as having had no period for 12 months in a row. although menopause can be induced by surgery or medical treatment, for most people, it happens naturally during midlife   typically between ages 45 and 55. it’s preceded by perimenopause, a period of about four to eight years when the ovaries slow their production of certain reproductive hormones. this can result in erratic fluctuations in hormone levels, launching a rollercoaster of symptoms that can continue into the postmenopausal years. hormone therapy replenishes some of those depleted hormones, particularly oestrogen and progesterone, and so smooths out that ride. what’s more, it can stave off osteoporosis and might provide other long term health benefits. women’s health research lacks funding   these charts show how women’s health research lacks funding   these charts show how but the popularity of hormone therapy plummeted in 2002 with the publication of an initial report1 from a long term us study called the women’s health initiative (whi). early analyses found that people who had been through menopause and who were taking oestrogen and progestin (a synthetic form of progesterone) had slightly increased risks of breast cancer, heart attack and stroke. in its wake, the number of prescriptions for postmenopausal hormone therapy dropped abruptly worldwide. in the united states, estimated rates fell from as high as 40% down to below 5%. susan davis, director of the women’s health research program at monash university in melbourne, australia, says global rates similarly slumped. subsequent work highlighted the substantial limitations and misinterpretation of the findings; data from subsets of participants in the whi and other trials even revealed contradictory findings, including lowered risk of heart disease and death associated with hormone therapy, and decreased rates of breast cancer for those taking oestrogen only therapy. scientists have been trying to set the record straight since. finally, in may 2024, a review2 gained traction in medical circles and the popular media. the authors, many of whom worked on the original 2002 paper, re emphasized that the hormone formulation, dosage and route of delivery in the whi trials differed from what is typically used today. for example, the therapy was taken only orally in the trials. today, the use of transdermal patches can reduce concerns about the blood clots that can be associated with oral delivery. a recent shift to hormones that are identical to the ones the body makes and the prescription of lower doses of hormones might further reduce risks, the authors note. researchers point to another important issue: most of the people enrolled in the whi trials were at least a decade into their postmenopausal years. at that point, research suggests, the sudden renewed presence of oestrogen might cause health problems. in other words, the timing of hormone therapy initiation might matter. actor halle berry advocates for us legislation that would increase menopause research.credit: tom williams/cq roll call, inc/getty and beyond managing menopause symptoms, there are long term benefits that could outweigh any risks. data since the late 1980s solidly back the use of menopausal hormone therapy to prevent osteoporosis in all age groups. “the big thing that was missed in this whole whi story was the benefit of oestrogen for fracture,” says davis. she has been investigating whether supplemental testosterone could also protect bones after menopause. for heart disease, the equation gets more complicated. if the therapy is started early, evidence suggests that it might prevent vascular disease. but, in people with vascular disease, researchers say, the therapy might worsen the condition. there are also emerging hints that well timed therapy can benefit brain health. at present, the exact benefits and risks of the therapy remain unclear, says davis. “depending on how you slice and dice and cherry pick the data, i could give you any story you want to hear.” her concern is that researchers continue to trawl big data sets without understanding the nuances and limitations of the data. guidance for menopause management around the world remains controversial, inconsistent and changes rapidly, specialists say. still, there is growing consensus that clinicians should “very seriously consider” hormone therapy for women within ten years of reaching menopause, or before age 60, if they have no contraindications, says joann manson, a women’s health researcher at harvard medical school in boston, massachusetts. although more research is needed, she says that early initiated hormone therapy might be safe and beneficial to take long term. a study3 co authored by davis even suggests that the benefits of initiating hormone therapy later in menopause might still outweigh the risks. how menopause reshapes the brain how menopause reshapes the brain wearable sensors, as well as implantable bioelectronic devices, could help to identify the optimal window for starting hormone therapy by tracking hormone levels in real time. some physicians caution against using the therapy during perimenopause because of the potential for high combined hormone levels during erratic natural fluctuations. one day, these devices might even dispense hormones on an as needed basis. still, some specialists point out, replacing hormones might not be enough. the ovaries are responsible for more than making oestrogen, progesterone and eggs. the small organs send chemical signals throughout the body, driving “hundreds of other factors with health benefits”, says zev williams, a reproductive endocrinologist at columbia university in new york. when the ovaries fail, says renee wegrzyn, director of the advanced research projects agency for health (arpa h), a government agency with a key role in the white house initiative on women’s health, “there are a lot of chronic health conditions associated with that”. so some scientists have a different idea   keep the ovaries working indefinitely. or nature 637, 782 784 (2025) doi: https://doi.org/10.1038/d41586 025 00069 4 correction 05 february 2025: an earlier version of this news feature misdescribed the role of arpa h in the biden administration’s white house initiative on women’s health research. rossouw, j. e. et al. jama 288, 321 333 (2002). article pubmed google scholar manson, j. e. et al. jama 331, 1748 1760 (2024). article pubmed google scholar taylor. s. & davis, s. r. lancet diabetes endocrinol. 13, 69 74 (2025). article pubmed google scholar dou, x. et al. aging cell 16, 825 836 (2017). article pubmed google scholar johnson, j. et al. am. j. obstet. gynecol. 230, 426 426 (2024). article google scholar allen, j. t. et al. menopause 30, 1002 1005 (2023). article pubmed google scholar yang, l. & toriola, a. t. jama health forum 5, e243128 (2024). article pubmed google scholar download references reprints and permissions menopause research is globally underfunded. it’s time to change that how menopause reshapes the brain women’s health research lacks funding   these charts show how menopausal chimpanzees deepen the mystery of why women stop reproducing omega 3 supplements slow biological ageing news 03 feb 25 x chromosome passed from mother to daughter influences brain ageing news & views 22 jan 25 rna molecule rejuvenates ageing mice by restoring old cells news 17 jan 25 scientists globally are racing to save vital health databases taken down amid trump chaos news 07 feb 25 these gaza scientists are keeping research alive amid war, destruction and uncertainty news 06 feb 25 ‘it is chaos’: us funding freezes are endangering global health news 06 feb 25 ‘research that touches the heart’: the 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associate or senior editor, nature health location(s): new york or shanghai   hybrid working application deadline: february 14, 2025 a... new york city, new york (us) springer nature ltd menopause research is globally underfunded. it’s time to change that how menopause reshapes the brain women’s health research lacks funding   these charts show how menopausal chimpanzees deepen the mystery of why women stop reproducing an essential round up of science news, opinion and analysis, delivered to your inbox every weekday. sign up for the nature briefing newsletter   what matters in science, free to your inbox daily. nature (nature) issn 1476 4687 (online) issn 0028 0836 (print) © 2025 springer nature limited

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supported by scientists are studying how to keep the ovaries working longer   and potentially, prevent age related diseases in the process. by alisha haridasani gupta and dana g. smith in march, the first lady, jill biden, announced a new white house women’s health initiative that highlighted a seemingly obscure research question: what if you could delay menopause and all the health risks associated with it? the question comes from a field of research that has started to draw attention over the last few years, as scientists who study longevity and women’s health have come to realize that the female reproductive system is far more than just a baby maker. the ovaries, in particular, appear to be connected to virtually every aspect of a woman’s health. they also abruptly stop performing their primary role in midlife. once that happens, a woman enters menopause, which accelerates her aging and the decline of other organ systems, like the heart and the brain. while women, on average, live longer than men, they spend more time living with diseases or disabilities. the ovaries are “the only organ in humans that we just accept will fail one day,” said renee wegrzyn, director of the advanced research projects agency for health, a government agency tasked with steering dr. biden’s mission. “it’s actually kind of wild that we all just accept that.” it is the ovaries’ truncated life span that also makes them such a promising site for experimentation. researchers think that prolonging their function, better aligning the length of their viability with that of other organs, could potentially alter the course of a woman’s health   and longevity research overall. dr. wegrzyn said she hoped the white house initiative, in which researchers and startups are competing for a slice of the program’s $100 million budget, will highlight the connection between menopause and longevity, while also attracting more funding and talent to the field.

 information for most women agree that menopause has its advantages and disadvantages. some relish the end of menstruation and concerns about unplanned pregnancies, while others dread the possibililty of hot flashes, moodiness, and other unpleasant symptoms. what some women consider a brief and barely noticeable phase in their lives can evolve into lasting changes and discomfort for others. now, a new paradigm around the biological processes of menopause is capturing the attention of a small group of scientists around the country. the primary question: can menopause be delayed in healthy women, allowing them to extend their child bearing years and perhaps even forestall some of the health risks and uncomfortable symptoms linked to plummeting estrogen levels? these questions can be controversial: some people believe that such research could lead to life changing benefits for women, while others consider menopause to be a biologically driven life stage that should not be pathologized by medical science. at yale school of medicine (ysm), kutluk oktay, md, phd, an ovarian biologist who is director of the laboratory of molecular reproduction and fertility preservation, recently added a new chapter to this conversation by publishing research on various possible outcomes when menopause is delayed in healthy women via ovarian tissue freezing. oktay, who developed and performed the world’s first ovarian transplant procedure with cryopreserved tissue for a patient with a medical indication in 1999, sees a future in which healthy women could use this process of freezing tens of thousands of eggs within the ovarian tissue to stave off menopause for as long as several decades or even prevent its onset altogether.