Slowing Down Ovarian Aging for Healthy Female Longevity

To keep up with the world’s rapidly aging population, the NAM launched the Healthy Longevity Global Competition, a multi-stage global competition designed to seek out bold, innovative, and breakthrough ideas that challenge the way we think about aging. The Catalyst Award, the first stage of the competition, rewards exciting opportunities that display prospective improvement in the mental, physical, and social well-being of individuals as they age. David Pepin is one of NAM’s 46 U.S.-based Catalyst Awardees. We hear from David, Associate Director of the Pediatric Surgical Research Laboratories of the Massachusetts General Hospital, and an Associate Professor of Surgery at Harvard Medical School, who speaks to the award-winning project seeking to extend the reproductive longevity and hormonal health of women as they age.

Can you share a little bit about yourself and your team)? How did you come to work together? What advantages does your interdisciplinary team bring?

I am the Associate Director of the Pediatric Surgical Research Laboratories of the Massachusetts General Hospital, and an Associate Professor of Surgery at Harvard Medical School.   My research focuses on the role of anti-Mullerian Hormone (AMH) also known as Mullerian inhibiting Substance (MIS) in the ovary and its application to infertility and reproductive longevity.
During work on a fellowship with Dr. Patricia K Donahoe, we discovered the contraceptive properties of this hormone. Recently, we have been exploring new applications of MIS analogs in women’s health, combining my expertise in ovarian biology with that of Dr. Donahoe’s in MIS biology and clinical translation.  

Please tell us about your innovative idea/project. Why it is particularly innovative, bold, and/or novel?

Women are born with a limited number of eggs, their “ovarian reserve”, which gradually gets used over time until they are depleted at menopause. Menopause is associated with many problematic symptoms as well as declines in bone and cardiovascular health. We aim to develop a treatment that slows ovarian aging, extends reproductive longevity, and preserves hormonal health in aging women. Aging is accelerated in the ovary, and eggs are increasingly lost over time either by being recruited to grow or by degenerating. We aim to slow this attrition by controlling the rate of activation of dormant eggs using MIS, a natural ovarian hormone that regulates this process. Thus, MIS may provide a novel paradigm of a hormone that combats ovarian aging and prevents or delays the negative consequences of menopause on bone, cardiovascular, neurological, and overall health.

What inspired you to develop your project? Was your original goal improving health for people as they age or did that become apparent later on in the process?

In our previous works, we have shown that treatment with high levels of MIS in mice can inhibit the activation of dormant follicles and prevent the growth of new follicles. We demonstrated that the MIS hormone could therefore be used as a contraceptive in several species. Because MIS acts on the first step of follicle activation, unlike oral contraceptives that inhibit the final step of ovulation, MIS has the potential of preserving follicles in their dormant state. We used this unique mechanism of action to protect the ovary from the “accelerated aging” that occurs during treatment with chemotherapy, which often causes infertility and premature menopause in cancer survivors. While ovarian aging is multifactorial and involves processes that are difficult to reverse such as DNA damage in the egg, we hypothesized that MIS used chronically may be effective in delaying normal menopause by promoting a larger ovarian reserve. In many species, reproductive longevity and overall longevity are intrinsically linked, and thus modulating follicle dynamics to maintain the ovarian reserve dormant could both extend ovarian lifespan and improve the health of women as they age. 

How might your innovative idea/project lead to a future breakthrough in the field of healthy longevity?

Longevity in women is uniquely affected by the hormonal changes associated with menopause, which accelerate the aging of bones, the cardiovascular system, and the brain. Furthermore, an increasing proportion of women choose to delay pregnancy. Twenty percent of women in the United States are choosing to have their first child after age 35; however,  two-thirds of those women will experience infertility oft due to low ovarian reserve (CDC). Therefore, there is an unmet need for a method that both extends reproductive longevity and preserves hormonal health in aging women. Delaying menopause could promote healthier aging by preventing declines in cardiovascular, neurological, and bone health along with the symptoms of insomnia and hot flashes associated with perimenopause.  

NAM is Seeking Applicants for its 2022 U.S.-Based Healthy Longevity Catalyst Awards!
Applications will be accepted from January 17, 2022, through February 28, 2022 at 11:59 pm EST. Applicants from all fields, backgrounds, industries, and specialties are encouraged to complete the unique and simple 2-page application to earn $50,000 USD in seed funding for their innovative projects.

How do you see your project advancing in the future?

In this study, we propose to use gene therapy to increase the levels of MIS and finely tune the rate of activation of dormant follicles to extend the reproductive lifespan in mice. We hope to generate proof of concept that ovaries treated with MIS using gene therapy can retain more ovarian reserve, and continue to produce sex steroids at an advanced age compared to controls. Should we demonstrate that MIS hormone-replacement therapy is effective at extending reproductive longevity in mice, the next step would consist in evaluating this strategy in non-human primates, which share a reproductive cycle similar to humans and are the only model which experiences true menopause.

What motivated you to apply to the Healthy Longevity Catalyst Awards? What advice would you have to other prospective applicants?

While our idea of modulating ovarian activity to delay menopause in women is high-risk, being completely untested, it may also be a high reward given the large impact menopause has on aging. A big motivating factor for us was the relative lack of focus on aspects of aging that are unique to women. Women’s health, and particularly menopause, has received little attention in the past, from either the pharmaceutical industry or granting agencies supporting this type of work in academia. As such, innovations in that space have remained relatively limited, which we interpret as an opportunity to have an outsized impact on health. We would advise other prospective applicants to consider sex differences in the aging models that they use.

Has this award changed your perspective on what healthy longevity looks like?

This award has reinforced our view that long-term reproductive health in women is key to healthy aging. It has helped us consider the translation of our findings from mice to humans.

David Pepin, Ph.D. is the Associate Director of the Pediatric Surgical Research Laboratories of the Massachusetts General Hospital, and an Associate Professor of Surgery at Harvard Medical School. Dr. Pepin is leading the NAM Catalyst Award-winning research on the role of anti-Mullerian Hormone (AMH) also known as Mullerian inhibiting Substance (MIS) in ovarian longevity.

Dr. Donahoe is the Director of the Pediatric Surgical Research Laboratories and Chief Emerita of Pediatric Surgical Services at Massachusetts General Hospital. Dr. Donahoe cloned the MIS gene in 1986, and her laboratory studied the regulation of its receptors and pioneered the use of recombinant MIS to treat ovarian cancer.

Researchers with project proposals can apply here in January 2022 when the Catalyst Award Application opens. To learn more about the NAM’s Catalyst Awardees, check out these stories. For more information about the global Healthy Longevity Global Competition, click here. We appreciate your support in advancing innovative solutions to promote health throughout the human lifespan. Email for questions about the award.

Sign up for updates