Our interviewee today holds that female reproductive aging, or ovarian aging, is accelerated compared to other organs and that it has a deep impact both on the lives and health of women and on our society as a whole. Nevertheless, ovarian aging continues to be underresearched, with only a handful of companies working in the field. Dina Radenkovic, a medical doctor, bioinformatics researcher, and health entrepreneur, heads one such company: Gameto, a startup that recently made waves after securing 23 million dollars in a round of funding.
Could you give us an overview of ovarian aging? What is it, what does it do to the female body, and how exactly can we measure it, considering that we think of it as premature?
The way we talk about it is in terms of function, not just cellular pathways. The reason our company is called Gameto is that we want to change the game of gametogenesis. Spermatogenesis is male gametogenesis, and it occurs throughout the lifetime, whereas female gametogenesis occurs while the woman is still an embryo. However, when women need to start using their ovaries, in the current social environment, this mostly happens relatively late, after they get an education, advance a career, and so on.
Yet, in standard gynecology, ovaries are often characterized as geriatric starting from the woman’s mid-thirties. Women experience a steep decline in the function of this organ. So, we say it’s an aged organ simply because its function is declining. That’s why we have the need for IVF, which only started about 40 years ago, and now it’s one of the largest out-of-pocket industries, and the demand is ever-growing because we’re pushing it to the edge in terms of age.
Organ dysfunction, or organ failure, is one way to characterize aging. In this paradigm, the first milestone is the decline in fertility, and the second is menopause. This is when you lose the function of your ovary and the production of the hormones that control a lot of your behavior and physiology. Menopause is so functionally important in the context of aging that the age of menopause onset is actually associated with life expectancy.
There have been studies that show that if you postpone the age of menopause by one year, you can increase life expectancy by 2-2.6 years. Interestingly, prior to menopause, women are more protected from many health conditions than men – for instance, from coronary heart disease. But after menopause, they start experiencing all those diseases of aging.
It’s like the stereotypical frail old lady with the cane, right? Your bones become weaker. You have increased risk of dementia, heart disease, and many other conditions, and you develop this syndrome of frailty. If you look at the diseases of aging in women, they all start with menopause.
This is what ovarian aging is: you’re 35 and your skin and brain are in perfect order, but your ovaries are already declining in function and that’s something that’s not happening to your male counterparts. Yes, there is this concept of andropause, but it happens relatively in synchrony with the function of other organs.
What we at Gameto are saying is that if this loss of function is the root cause of both infertility and all those diseases that occur with menopause (and there’s also early menopause, this extremely problematic condition called primary ovarian failure, when your ovaries stop working in your twenties and thirties), let’s develop therapeutics that will solve this, that will rescue this function.
To summarize: if you look at ovarian aging, be it in terms of follicular count or the quality of the eggs, ovaries share many aging pathways with other organs, but the function of the ovaries declines faster, and that’s why we say that the ovaries age faster than the rest of your body.
Do we have any idea why ovarian aging is so different?
I wouldn’t say it’s necessarily different. The reason why a lot of the interventions for aging work in the ovaries is because the same pathways are involved, but the actual answer to your question is that we don’t know. For instance, why does the thymus age faster? The truth is we have no idea. If you want me to speculate, using the antagonistic pleiotropy theory of aging or the hyperfunction theory, you could argue that ovaries are hyper-stimulated. We lose many follicles to get the one good mature follicle per month.
It’s not optimized to preserve function, it’s hyper-stimulated to ensure that one good egg is mature, and this one good egg will control all your cycle and physiology. This hyperfunction in the early stages is probably optimal for reproduction, but as the hyperfunction theory suggests, later on, hyperfunction leads to dysfunction.
The reason why it hasn’t been “fixed” by evolution is because evolutionary forces mostly work during the reproductive period. But the society has changed! Today, women can expect to live to 90 or 100, if they don’t smoke and adopt a healthy lifestyle. So, they spend two thirds of their lives infertile, unable to have children, and also half of their life in this state of post-menopausal poor health. And that’s what we are trying to solve.
Because of accelerated ovarian aging, women in the modern society have to accept compromises they may not wish to make, like should I take this job, or should I have a baby? Suppose you want to do both, but biologically, you have to make a choice, and that’s what we hope to change.
How does this accelerated reproductive aging drive gender equality? What would be the societal implications of extending reproductive healthspan in women?
I would call it the root cause of gender inequality. I would love to see a future where a young couple in their twenties can pursue their careers, travel the world, do all those things they want to do, and then start a family in their forties. Today, most women are unable to do that, so men have the advantage. Leveling the field would make the game fairer, would empower women and allow them more choice.
Childbearing and childcare are also expensive, and not everyone can afford it when they’re young. So, we don’t want to tell people what to do with their lives and when to have children, we just want to give them more choice, that’s our company’s mission.
This year in the United States, we have the lowest fertility rates on record, and that’s not necessarily good because a lot of women are postponing childbirth or deciding not to have children at all because of various difficulties. We want to ensure they can have children when they feel ready, mature, when they feel that they found the right partner or that they’ve done what they wanted in terms of career. To me, this is very important. I think this would enable more women to participate in the workforce, to get education, to contribute to society, which would be good for society as a whole. I would like to have it myself as a woman, and my sister to have that option. I would have wanted my grandma to have that option.
Female aging is known to be underresearched. Is this a part of the broader gender bias in medicine?
I think things are moving slowly in the right direction, but we need to do more. We must have more women in high-profile positions. As there are more women, and as they climb up the corporate ladder, they will talk more about this issue. Before we had representation of women in those positions, these issues were a taboo. Women create the market; women talk about women’s problems. It might be hard to understand women’s issues if you’re not experiencing them yourself. You might not necessarily have bad intentions; people can be simply unaware of problems that are not theirs. That’s why I support diversity and inclusion.
It is also very important to have serious biotech companies in this space to show that this can be backed by real science, that proper therapeutics can be invented, that it can be profitable for investors.
So, is this gender bias still around?
I think it is. For instance, because I’m a woman, people would always think I’m a nurse, not a doctor, and so on. Yes, it is still out there, in some areas more than others. It’s changing slowly, but we need to keep pushing for it.
We need to encourage more people to work in this space, both on the biotech side and in service delivery. We’re talking about half the population that are experiencing these problems, and it’s horrible that we haven’t done anything about this.
For instance, every decade, we add two years to life expectancy, but we haven’t pushed back the onset of female reproductive aging an inch since we started keeping medical records in the 1800s. As long as we keep living longer without changing this, we’re just worsening the gender inequality. This is so unfair! When I started working in the aging field, I thought that this is a problem I must solve.
Looks like ovarian aging today is perceived like organismal aging was perceived until recently – something that we just thought was normal.
Premenopausal hormone levels seem to be protective for women. On the other hand, there are estrogen-related cancers, and hormone replacement therapies have been linked to increased risk of cancer as well. How sure are we that extending this premenopausal hormonal landscape would do more good than bad?
It’s not like we’re building a drug for everyone, and everyone should start taking it. This is not what we’re doing. We’re developing biologics that are going to solve some of the problems like infertility or diseases that occur after menopause. Hopefully, they will get approved and licensed for specific indications, like infertility, primary ovarian failure, and physicians would prescribe them based on the clinical need.
As to the studies, there was this study where the median age of patients was 63, I think, and they found a very marginal increase in the risk of breast cancer. On the other hand, the women also became more fit, they had improvements in some other conditions.
The answer is that it will obviously require a conversation between a patient and their physician, an assessment of what’s best for the patient, for how many years they need to take it, when to stop and so on, based on the clinical picture. It’s very hard to generalize, but I think overall, if we could provide personalized dose delivery and to slow some of the pathological processes that occur with menopause, we could find a way to get the best of both worlds – that is, to prevent diseases without necessarily causing the increased risk of cancer.
You could argue that if you push the age of menopause by continuing hormone exposure, what will happen will be similar to men and prostate cancer. Prostate continues to grow because men don’t go through a quick andropause. They don’t lose 80% of their hormones within one year, so their prostate continues to be constantly exposed to androgens. That’s why there is a saying that most men will die with prostate cancer, but not of prostate cancer. You could argue that a similar picture might occur with women – they won’t die of it because they will be biologically younger, and fitter. But yes, we could see increased incidents of some cancers.
I think, the regulators and the clinicians have the right to be cautious and to give those therapies to women who need them and for the amount of time they need them, because yes, of course, with every therapy you have the upside and the downside, and it’s about the overall benefit.
Let’s talk about Gameto. You haven’t released a lot of details about what you’re going to do and what’s the science behind your strategy. Could you walk us through this? For instance, cellular reprogramming is a vast topic, so what exactly are you going to do with it?
I think we’ve disclosed everything that we are working on right now. We’re a very early-stage company, but we use cellular reprogramming to make ovarian cells and ovaroids. And then we use ovaroids to make biologics for infertility in ovarian diseases. We’ve published a paper and we’ll publish another one, hopefully, this year, once the patents are converted, and we want to keep publishing everything as soon as we are legally able to, because we’re pushing the boundaries of an interesting area of science.
In terms of the biologics, we have two lines that we’re working on. The first one is fertility. We’re testing a biologic for IVF, so that instead of giving stimulation with injections before we extract the eggs, we’d be able to make it a full in vitro experience, making the cell extraction shorter, safer, more effective. That would allow women to undergo IVF for a little bit longer, as long as they’re pre-menopausal. My co-founder and chairman is Martine Ruszkowski, he’s a global leader in the fertility space, and we collaborate with his chain of fertility clinics, the largest in the United States.
Later down the line, we’re working on a biologic for primary ovarian failure, which is early menopause, and that could also help other women with menopause. Right now, we have a sponsored research agreement with George Church’s lab at Harvard. A lot of the basic science in cellular reprogramming comes from Harvard, and then the more clinical work is done within the company. We have more things to tell, and as soon as we are legally allowed to disclose, we surely will.
Are you aware of any competition? I think just a handful of companies are currently working in this space.
I wouldn’t call that competition. I would like to have more people working in this area. There are so many problems: we have endometriosis, PCOS (polycystic ovarian syndrome). For endometriosis, there’s no therapy. For PCOS, we have seen some use of metformin, but it’s not even licensed for this. In menopause, there’s not much innovation as well. Then, we have IVF. There’s just so much to do, and only a handful of companies, so I would love to have more people in, more talent, both on the science side, and in the industry. This is something that’s affecting half of the population, and we only have three or four companies working in this field. We can’t do it all by ourselves.
Also, in order to grow, you need an ecosystem, a talent pool. Now, it’s easy because we’re a small company. But if we, hopefully, grow and become a big company developing multiple biologics, we will need to hire scientists who are interested in this space and educated in it. Unless there’s relevant funding for academia, where are we going to find them?
I see everybody working in this space as my partners, my collaborators, because we’re trying to establish ourselves as a credible field and to attract top talent, and today, it’s like a nuclear war for talent. It’s really hard to recruit people. I think we’re all helping each other, and I would love to see more companies entering this space.
What are your thoughts about the situation in the longevity field in general? Are you focused solely on female reproductive aging, or are you, let’s say, a longevity enthusiast?
In the company, we’re focused on female reproductive aging, but I have spent a lot of time in the aging field, and I am passionate about it. I think what has happened over the last few years has been mind-blowing. We’ve seen huge organizations taking shape. In the past, if you said you worked in the aging field, people would not understand you. What is longevity medicine? Today, it’s becoming a respectable, interesting, cutting-edge area.
I think this is extremely important, and I’m so happy for the field, but as a company, we will not be able to do everything. So, I want us to stay focused on the diseases caused by ovarian aging. Still, I’m obviously extremely passionate about everything aging-related.
I love to follow all the other aging companies, to read about their work, I cheer for them. And I think we can make an important contribution to the field, because a lot of what we’ve learned about ovarian aging could be translated and shared.
Various lifestyle interventions might currently be our best bet to slow aging. Do you think any of these, such as caloric restriction or exercise, can work against ovarian aging?
Being generally healthy, having good metabolic health, maintaining healthy weight and low levels of inflammation should be just as good for ovaries as for other organs, but sadly, I don’t think these interventions are sufficient to have a marked effect on this accelerated type of aging that results in the loss of ovarian function.