Reproductive Longevity
It’s about family. It’s also about women’s healthspan.
Back in May, I had the privilege of attending a talk on reproductive longevity hosted by early-stage VC fund Fifty Years. As a woman, I was personally interested in learning about the latest advances in the field. As an investor, I was curious about opportunities in this space. What follows is a roll-up of key takeaways from the talk, summary research on the macro trends, and startups to track going forward. (Author’s note: bio-tech is outside my technical expertise. Feedback is welcome!)
Talk Highlights
Dr. Jennifer Garrison, Director of the Global Consortium for Reproductive Longevity and Equality and Assistant Professor at the Buck Institute, focused on the impact of menopause on women’s overall healthspan. While women have a longer average lifespan than men, more of that time is spent in a frail health condition. The statistic that dropped my jaw: for a 75-year lifespan, women are frail for the last 34 years while men are frail for the last 26 years. This difference in frailty is likely due to negative effects that start once women enter menopause. Further rubbing salt into the wound: early onset menopause shorts women’s lifespan. Ovarian aging affects the aging of other tissue, and menopause speeds up cellular aging by 6–10%! Men’s reproductive organs decline with the rest of their tissues aging (in their 50s), while women’s reproductive organs decline a decade earlier. (For additional data, see the Buck Institute’s whitepaper on reproductive longevity.)
The other surprising learning from Dr. Garrison’s talk: only humans and four types of whales go through menopause. It is NOT something all mammals do. The current evolutionary theory for this is called the “grandmother hypothesis.” Whales are highly social animals and raising whale babies is resource intensive. It’s useful for the survival of species to have post-menopausal females around to help care for offspring. Summing up those learnings: historical group dynamics where females were the caretakers may have led women to evolve into a form with the unintended side effect of an extra decade of frailty.
I attended the talk thinking I would learn about technologies that enable women to have children later in life. Instead, I got schooled on the importance of reproductive longevity for overall healthspan and lifespan. Good news: it’s not all gloom. Researchers conducted an experiment implanting young ovaries into mice and saw the predicted increase in mice lifespan. What’s more interesting is that young ovaries without oocytes (eggs) extended mice's life the longest. (The working hypothesis is that there is an undiscovered signaling pattern between the ovaries and the brain.) Move over blood boys –reproductive robustness may be the new longevity hack.
Macro Trends
The overarching macro trend is the decline in fertility rates. The latest data from the 2022 UN Population Prospects predicts the global population will peak in the 2080s at ~10.4 billion people. Note that the world’s population is expected to surpass 8 billion by the end of 2022. In the 65 years from 1950 to 2015, the world population tripled (2.97x). Yet over the next 65 years, it will only grow another 1.4x. What was once a problem for developed western democracies is now a global problem.
The decline in fertility rates has led to an even harder population problem: demographic pyramid inversion. The demographic shift from a population dominated by young healthy workers to one dominated by infirm elderly retirees has devastating impacts on the economies of those countries. (See the IMF’s analysis on Japan for the relationship between its demographic decline and its lost decades of stagnation.) The most dramatic demographic statistics actually come from China, whose population may have already begun its decline in 2018.
The United States has largely avoided this demographic inversion thanks to immigration. (Author’s aside: America can also thank its immigrants for their help out-pacing the world on innovations and producing over half of its billion-dollar startups! Check out the recent piece from Dr. Graham Allison and Eric Schmidt on policy arguments to leverage this advantage to its fullest.)
In the US, one-quarter of couples who need IVF to conceive actually receive the treatment [ref]. The definition of infertility as a medical condition for insurance purposes varies by state, with only 14 states mandating insurance providers cover assisted reproduction treatments [ref]. A federal law recognizing infertility as a medical condition with a standard of care that includes IVF would help those couples who want children to afford the necessary care to have them.
Underlying Factors
What are the drivers behind these macro fertility trends? General social arguments center around access to contraception and increased education leading to decreasing birth rates [ref]. Going a layer deeper, the economic data shows a correlation between restrictions on housing and lower fertility rates [ref]. There are also biological root causes, linked to environmental factors, that impact both female and male fertility.
Many great scientific findings are a combination of accidents and keen observation (e.g. the discovery of antibiotics). The plastics-based endocrine disruptors share a similar story. BPA’s toxicity to human reproduction was discovered by a researcher studying mouse egg quality. On average, mice have 2% chromosomal abnormalities in their eggs. The mice in this study jumped up to 40% abnormal eggs due to BPA that had leached into their water after their bottles were run through the hot dishwasher. Heat, acid, and UV light can cause chemicals to leach from plastic over time. For human egg quality, women in the top quartile of blood BPA levels had a significant number of abnormal embryos. Reducing exposure to BPA and phthalates is a straightforward measure to improve the odds of a healthy pregnancy [ref].
There has been a multi-decadal decline in male sperm counts [ref]. The staggering 52% decrease has been hypothesized to be a result of environmental exposure to endocrine disruptors [ref]. Male-factor infertility is the underlying cause in ⅓ of couples seeking reproductive assistance, and even more disheartening the root cause of male-factor infertility in 50% of cases is unknown [ref]. There is a scarcity of knowledge to empower men and reverse these trends in sperm quality. I look forward to science and startups filling in this critical gap.
Solution Space
Fertility decline is a multivariate problem that cannot be solved by policy alone. People are choosing to have fewer children AND they are also waiting until later in life to have them. What are the technological solutions that can help humanity continue to grow in a way that empowers individuals?
The long-term moonshot is artificial wombs. (See “Womb for Improvement” from Works in Progress for an overview on the topic.) The optimism for the technology stems from the 2017 Nature article showing a lamb fetus growing in a bag [ref]. In the near future, artificial wombs could be used in the later stages of fetal growth, to increase the survival of very premature babies. However, I am bearish on the time horizon for artificial wombs covering the full spectrum of fetal development. My rationale stems from all the unknown unknowns of maternal epigenetics. We don’t yet understand how the artificial womb environment may impact gene expression; there is potential for life-long negative impacts on the children. The regulatory and ethical hurdles will abate womb-tech progress.
In the medium term, there’s an experimental intervention to improve (and even reactivate) ovarian function by injecting platelet-rich plasma (PRP) into the ovaries [ref]. PRP has demonstrated efficacy in other specialties: it’s used by dermatologists to accelerate wound healing and by orthopedic surgeons to treat osteoarthritic knees [ref]. The hypothesis for PRP-based ovarian rejuvenation lies in the ability of PRP’s growth factors to stimulate dormant follicles in the ovaries. Clinical trials are ongoing to determine the efficacy of this experimental procedure.
The short-term answer for women’s reproductive longevity lies in evidence-based supplementation. The supplement studies focus on egg quality for reproductive purposes, but their findings are likely transferable to prolonging ovarian function. I believe this is a reasonable logical extrapolation due to the importance of mitochondria to both egg quality AND ovarian function. Many of the recommended supplements help energize the mitochondria (such as CoQ10, N-Acetylcysteine, and NAD+ precursors). The remainder of the supplement recommendations fall under antioxidants (Vitamins C, D, ALA, and melatonin) or the testosterone precursor DHEA (only recommended for women with diminished ovarian reserve). The book “It Starts with the Egg” provides a comprehensive summary of the research behind the supplements and the strength of the data. Disclaimer: this is not medical advice. Please consult your doctor before bio-hacking and consider working with a doctor to understand your supplement needs.
Of note, the longevity community favorite (NAD+ precursors) was missing from the book, as studies showing positive effects of NMN and NR on the fertility of mice only started coming out in 2020 [ref]. Not all interventions for longevity will have a positive impact on reproduction. Men who take off-label metformin for longevity were floored by a recent study showing a link to birth defects in boys whose fathers were on metformin.
Companies to Track
Pitchbook highlights fertility technologies as an “Emerging Space,” but most of the 56 companies in there are focused on diagnostics and fertility tracking (e.g. Modern Fertility), with that wave of companies peaking a few years ago. At the end of her talk on reproductive longevity, Dr. Garrison gave an estimated time horizon for the first therapeutics to emerge in 3 to 5 years. In the meantime, there are exciting companies to track now: Gameto has an ovarian cell line they are utilizing as a platform to develop and test therapeutics for reproductive longevity, Yuva Biosciences has a compound to target mitochondrial biogenesis, and Dimension Inx is leveraging precision bio-printing to create an artificial ovary.
Ivy Natal and Conception are working to create eggs from stem cells, which would enable women with primary ovarian insufficiency and gay couples to have genetic children. They have demonstrated the process for mice and chickens. It’s a long way to go before humans, but I am more optimistic about their timeline than I am for artificial wombs. Even though this is a harder problem, it likely has fewer regulatory hurdles.
Conclusion
The flippant response to the megatrend of demographic decline is to simply say ‘have more babies’ (or build better robots). It’s not that simple. Our environment is contributing to the problem of fertility decline, with BPA as the most dramatic example of plastics harming our DNA. The environmental factors are negatively impacting male sperm quality too. Men are part of the fertility equation that’s been understudied, thus presenting a wide-open opportunity space for researchers and founders.
In working on technology solutions for fertility, we are also unlocking increased healthspan for women along the way. Today, women can leverage extensive research on supplements to improve their ovarian function. In 3–5 years, we’ll see the beginnings of a new wave of therapeutics for reproductive longevity. And we’re seeing technology to unlock genetic children for gay couples within the next decade. Artificial wombs for full gestation of humans remain in the distant future, facing both science and regulatory/ethics hurdles.
While these are challenging problems, there is low-hanging fruit too — we all should be taking better care of our mitochondria!
Prime Movers Lab invests in breakthrough scientific startups founded by Prime Movers, the inventors who transform billions of lives. We invest in seed-stage companies reinventing energy, transportation, infrastructure, manufacturing, human augmentation and agriculture.
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