Melanie Cole (Host): Welcome to Better Edge, a Northwestern Medicine Podcast for physicians. I'm Melanie Colon. Today we're highlighting research on new molecular mechanisms for ovarian aging. Joining me is Dr. Francesca Duncan. She's the Thomas J. Watkins Memorial professor of reproductive science and an associate professor of reproductive science in medicine in the department.

Of obstetrics and gynecology at Northwestern Medicine. Dr. Duncan, it's such a pleasure to be speaking with you today. To start, when we think about ovarian aging, why has it become such a critical focus in reproductive and women's health research right now? Can you walk us through the current understanding of how ovarian reserve is really established And then progressively lost over time?

Just give us a little overview.

Dr Francesca Duncan: Yeah, so Melanie, I've always been really fascinated with ovarian aging because the ovary is really one of the first organ systems in the human body to show overt signs of aging, And this really begins to happen in women starting in their early thirties. So women are born with a fixed number of eggs in their ovary, and That is gonna dictate the reproductive lifespan of that individual.

And with age, there's a natural winnowing of this reserve, And this results in a loss of egg quantity and quality. And this has really important clinical ramifications. If we think about that. It's gonna have an impact on fertility, but also these eggs as they develop, they produce really important hormones like estrogen and progesterone, which are important for normal.

Physiology and overall health. So you can imagine with ovarian aging, there's really tangible consequences for fertility, endocrine function, and overall health. And so that's really why, uh, it has gained a lot of traction and attention, um, for women's health.

Melanie Cole (Host): I agree, and it's such an interesting topic. So how might the presence of multinucleated giant cells in aging ovaries influence your clinical approaches to fertility preservation, hormone replacement therapy? As you said, there's so many avenues here.

Dr Francesca Duncan: Yeah, so when we, as I mentioned, the sort of the main driver of ovarian aging is this loss of the number of eggs in the ovary and their quality. And so for many, many years, a lot of focus on reproductive aging and ovarian aging research has focused on what's happening to the eggs themselves.

But our lab has really shifted this focus and started to think about what's happening in the environment of the ovary. So the nest in which these eggs develop and how does that change with age? And um, several years ago when we were just looking at what is in the ovary, and actually an undergraduate student in the lab made this observation that there are these really unique.

Population of cells in the aging ovary, um, that are never present in a young ovary. And so in biology, if you ever hear something where something is present or absent in that sort of black and white stark contrast, you have to pay attention because. Biology is typically very gray scale.

So we started to become interested in what are these cells that are always present in an old ovary and they're never present in a young ovary. And it turns out that these are these multinucleated giant cells, which are a type of macrophage or immune cells that are typically found in tissues where there's chronic inflammation.

So for example, we can see it in, um. Um, uh, foreign body, giant response. So if you've had an implant, um, typically there'll be immune cells that come around that implant to try to remove that foreign body from the cells. So that's a highly inflammatory, um, response. For example, in tuberculosis, you'll see these multinucleated giant cells, they're coming in there trying to get the bacteria, um, surround the bacteria and protect the tissue from that bacteria.

And here we. See in the ovary, in an aging context, in an organ, And it's normal physiology, this really unique population of cells that are found in this aging ovary only in old ovaries and not in young ovaries. And really these are a sign of chronic inflammation. So we made this discovery 10 years ago, and it took us 10 years to have the technology to be able to really, truly understand what these cells are.

Yeah,

so let me just tell you really quickly a little bit about what the discovery that we just made. So what's been really challenging about these cells, um, is that they have a, um. Basically been quite elusive in terms of the technologies that we have available to us to probe them.

So for example, we have methods in the lab where we can look, it's called single cell sequencing, And we can look at individual cells And what they're expressing. But these multinucleated giant cells are very large cells and they're hard to get at with these technologies. So we actually developed or used methods where we can cut out these particular cells from the ovary.

Study what they're producing and expressing specifically. So we know that we're getting a signature just of these multinucleated giant cells. And what this enabled us to do is to figure out that these cells have very unique characteristics. They're making a, they're using a lot of energy, um, they're using a lot of mitochondrial function and they have a very, uh, specific inflammatory signature.

They have degradation processes going on. So that tells us that they're in the ovary trying to get rid of something. They're trying to degrade something That is there. Um, and we've been trying to figure out what That is. Um, again, they're typically, these cells are present where there's chronic inflammation.

They're trying to get rid of debris, um, in a tissue. And so we're really trying to understand now what is that debris that's. Accumulating with age And the ovary, and This is very similar to, for example, if you think of neurodegenerative diseases like Alzheimer's or Parkinson's, where you'll have accumulation of debris products, um, cellular aggregates that accumulate, for example, in the brain and lead to tissue dysfunction and diseases like Alzheimer's and Parkinson's.

So very. Similarly, the ovary is a really dynamic organ and it actually accumulates, we don't actually think about this a lot, um, but it accumulates a lot of debris products over its normal function, um, in a woman. And we think that this accumulation of debris, um, is what's causing these multinucleated giant cells to come in to try to get rid of that debris.

Um, And in doing so, they're creating a, a fibroin inflammatory loop. That's actually driving the aging of that organ. And so you're absolutely right that if we could potentially identify the debris, um, that's in the ovary and selectively remove it, that could have really strong therapeutic potential, um, to remove this kind of, uh, sort of waste or cellular waste of that organ and keep it in a youthful state.

And so we think that the debris itself or these multinucleated giant cells will serve as a really, uh. Great. A strong therapeutic target for ovarian longevity.

Melanie Cole (Host): That's really cool. And the implications are, are really, really big. So when we think of the patient populations that this could benefit the conditions where this research could have the most immediate impact. I mean, are we looking at fertility, preservation, cancer patient's? What are we looking at?

Dr Francesca Duncan: So I, that's super important. I think what's really important to realize is, as I mentioned, the ovaries doing two major functions. One, it's producing the eggs that are gonna lead to fertility, but at the same time, it's also producing the hormones that are going to lead to endocrine function, which has all of these downstream overall.

Consequences. So if we can preserve the functioning of the entire organ by maintaining the environment in which these eggs are developing in a healthy state, we're going to end up having a dual benefit where we can extend fertility, but also endocrine function. And so this can be important for, uh, obviously women as.

They age. But as you also alluded to other conditions where we might start seeing these fibroin inflammatory processes increasing with age, and there are many conditions where This is the case. So for example, polycystic ovary syndrome, late effects of chemotherapy and radiation like you're talking about in the fertility preservation population, but also in endometriosis where we know that there's an inflammatory reaction, um, within the ovary.

And so where our research needs. To go is to really understand what are these MN GCs, are they present in all of these other conditions beyond ovarian aging and these, you know, pathologies or other conditions like late effects of radiation and chemotherapy, to see how broad such a therapeutic could actually be.

Melanie Cole (Host): Wow. So along those lines then, Dr. Duncan, since you've mentioned that ovarian aging isn't just about fertility. Speak a little bit about how it intersects with long-term outcomes for health for women like cardiovascular disease, bone health. I mean, that's obviously a big one. Cognitive aging as you were speaking a little bit about before, is it emerging?

Do you see it emerging as maybe an early biomarker for overall biological aging for women?

Dr Francesca Duncan: I think This is a. Billion dollar question. So as the ovary ages, as I said, it is one of the first organ systems to age. Um, and I think a really important question is what is that interplay between the ovary and systemic health? And as the ovary starts to age, does it set off a negative series of.

Sequelae that trigger aging in other organ systems. So that's a little bit separate to what you asked me because that's sort of an indirect question. Is one organ starts to age and produce inflammatory factors. Does that signal to other organs and trigger the aging process in those other organ systems?

Um. So that's one question. The other question that's more directly to address your question is we already know that the ovary as these follicles that have the eggs, uh, grow, they're going to produce estrogen and progesterone, which are really important gonadal hormones that signal to these downstream organ systems.

So we know that estrogen regulates cardiovascular health, bone health, immune health, cognitive function, sexual health, skin And so forth. So just the. Amount of systems that the ovary regulates. Uh, we know by virtue of that fact that when we go into menopause or if we lose ovarian function early, that's going to have all of these other, uh, effects on these other organ systems.

So if we can extend ovarian function, we think that that could confer a broad health effect on these other organs. I was also discussing, I think again, what are the signals coming from this organ that's aging earlier than these other organ systems? Is that somehow causing, uh, signaling to start aging across the body?

And can we detect this systemically? Um, can we have a biomarker like you said, that says your ovary is of this age and This is predictive of these sorts of outcomes. So very exciting research on the horizon.

Melanie Cole (Host): Wow. It certainly is. And as we think of infertility, what about risk strategies for reproductive health and do you see this And the MN GCs and their unique properties and signatures reshaping our understanding of this reproductive aging and really affecting the world of infertility?

Dr Francesca Duncan: I think what's attractive here is that you have a target in the ovary that if we could keep the whole ovary. In a healthier state. So if we could remove this debris, the cellular debris, so just like we think about cellular aggregates and Alzheimer's or Parkinson's, if we can get rid of that debris, that would keep the environment in which these eggs are developing and producing hormones healthier longer.

Um, And so I think there, that's really a, a. That would be transformative because we're really protecting the entire organ and keeping the organ in a youthful state, not just targeting one aspect. So we're not just freezing eggs to preserve fertility, and we're not just doing hormone replacement therapy, uh, to give back hormones.

So we're actually keeping the whole organ functioning. Now, these MN GCs are highly, uh, as I mentioned, associated with. Tissues where there's chronic inflammation And we believe that they are producing and secreting certain profiles, inflammatory profiles that we can actually detect because they're secreted. Um, and So, it will be really important in the future to see if we can detect as a biomarker, as you mentioned, what is this ovary producing and secreting can we detect that in the blood?

And that's gonna be really transformative because right now, as a field, we have no. Conclusive marker of ovarian aging. So for example, we can look at egg number, um, at a given moment in time, but that really isn't giving us a comprehensive measure of the aging of this particular organ, which has such important clinical consequences.

So looking at, uh, factors like mmcs that are producing and secreting molecules, if we can get a specific signature, um, that will be really important for biomarkers of ovarian aging and. Overall health.

Melanie Cole (Host): How now, Dr. Duncan, as we think of how fast we're advancing in different aspects of medicine, are there novel technologies like single cell sequencing, AI driven modeling that are changing how we study ovarian aging? Do you see that headed in that direction?

Dr Francesca Duncan: Yeah, so I think what's really exciting, um. Is to see innovations in our thinking matched by accelerations and advances in the technologies, um, that allow us to probe what's in the ovary. So one thing that you might not know is that it is now, you know, 2026 And we still don't have a really good understanding of all the cell types that are in the ovary.

That's wild. Um, and you know, it's really because I think for a few things, again, technologically. Uh, limitations, but also the ovary has always been largely focused on the eggs because Those are really the critical cells that are the functional unit of the ovary. But it's only now that we're understanding how important the rest of that organ is to the function of those eggs.

And we finally have technologies like single cell technology, transcriptomics, proteomics, metabolomics, that allow us at a single cell resolution to actually define what's in the ovary. And the other thing about the ovary that I find really exciting is that it's very dynamic So, It is undergoing huge changes across development, across aging.

And then if you think about it, every 28 days for women in their menstrual cycle, that ovaries is undergoing tremendous development and remodeling. So it's an incredibly dynamic organ. And only with current technologies are we beginning to understand what are the cells that are in there, what are they doing, how are they changing with age?

Can we target them?

Melanie Cole (Host): That's what makes this research absolutely fascinating is because it's such a dynamic organ and changes every month as we all well know as women. So what role do you see OBGYNs. In translating these findings into patient care or clinical trials, take us from bench to bedside, as we've discussed all of these, these options and these models and things where it could be headed.

How do you see it translating? What's your vision?

Dr Francesca Duncan: Yeah, I think the bench to bedside. Um, so going, you know, what we do in the lab to how do we translate that into patient care, um, for me is one of the main drivers that, that get me waking up in the morning and going to work. Um, and I think at, you know, being at a place like Northwestern where there's such an integration between the basic scientists And the clinicians really allow us to make sure that the discoveries that we make.

At the bench can go to the bedside. And so we're doing that, um, in several ways. Um, first we really wanna make sure that what we observe in a mouse model isn't just a mouse specific phenomenon. Mice are incredibly valuable, important research models for reproductive aging. But again, we need to make sure that we're.

What we see in a mouse is actually relevant to what's happening in human. And so we have been partnering with our clinical colleagues, um, to be able to access human material, uh, whether that's ovarian tissue, whether that's follicular fluid, which is a microenvironment or readout, um, of the ovarian environment, serum samples, And so forth, to be able to translate our work And what we observe in the mouse.

To the human and we've been able with those resources to show that we're studying phenomenon that are highly relevant to human and very conserved. The other thing that we need to do is to start translating this work again into clinical care. And so one of the technologies that we're using, so as.

Part of this inflammatory environment that the mmcs create. This creates a stiff organ, um, because of fibrosis. And we actually have used models, ultrasound based, uh, technologies where we can actually go into the clinic And we can measure the stiffness of the human ovary in real-time. And so right now what we're trying to do is say, how does that measurement.

Correlate to outcomes of women who are potentially going through assisted reproductive technology. So like IVF, but also women who have a, a genetic predisposition to ovarian cancer because we know the aging ovary is actually a very permissive niche, uh, for ovarian cancer, uh, metastasis. And so we wanna see whether or not the stiffness or inflammatory environment of the aging ovary truly has a prognostic value.

So. It's great to do solid science and have high impact papers, but that only goes so far. We really need to make sure that we're translating our findings And that, you know, being at a place right at Northwestern where you can do That is, is fantastic. And I also think, um, another vision is to have, You know, partnerships with broader community, so startup companies, fem tech industry, to make sure that the advances that we make it in the bench can actually translate into to healthcare.

Melanie Cole (Host): Come on now. Dr. Duncan, you are doing really important work. I mean, when we think of those implications, they're broad and far reaching, and that's so important. I know that you are going to really get out there and, and advance women's reproductive technology and, and our knowledge so much as we wrap up here.

This is such a great topic. This has really been an exciting interview. Looking ahead. How do you think our understanding of the management of ovarian aging and these other broader reaching implications will fundamentally change? And what would you like to see happen? Give us your key takeaways for other clinicians.

Dr Francesca Duncan: So I think we have to really. I think we know so little about the ovary. Certainly we know how it produces eggs and how those eggs lead to fertility. We know the basics, understanding of endocrine function, but there's so much that we don't know And we need to harness the technologies that are currently available to us And that are constantly evolving to give us a deeper look at what's happening in the ovary.

And what I wanna end with is that. Um, I am, as I'm getting older, um, and sort of tracking my own reproductive function, I'm extremely interested in the postmenopausal ovary and I think we've all, for a long time thought that the postmenopausal ovary is sort of a dead organ.

It's just sitting there, it's quiet And it's done its job. And I will sort of leave you with some tantalizing concept that I think that that postmenopausal ovary is actually. Far from quiescent. Um, and we're only beginning to understand what is it still doing? What is it producing, what is it secreting?

How is it signaling to the rest of the body, and is it truly an innocent bystander in the aging process? And so I think we need to sort of suspend our assumptions, um, and really take new technologies to, to truly understand the complexities of this organ.

Melanie Cole (Host): Quiescent is such a good word. And as somebody who is post-menopausal, That is such an interesting thought process, And so you'll have to let us know when you do more research on that because I will be so interested to hear that. Thank you so much, Dr. Duncan. What a great episode this was.

Thank you so much for joining us and to refer your patient. Or for more information, please visit our website at Breakthroughs for physicians.nm.org/obgyn to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine Podcast for physicians. I'm Melanie Cole.