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A recent paper published in Nature Aging dives into the gene expression differences between young, middle-aged, and older human ovaries and tests possible interventions to slow down their aging processes [1].

An underexplored area of human aging

Female reproductive aging remains a relatively unexplored area of study. With people living longer and females postponing childbearing, there is a need for research into slowing it down.

The ovaries are indispensable organs in female reproduction, essential in hormone production and fertility. [2] Compared to other organs, ovarian functioning ceases relatively early in life, at around 50 years. However, the decline in its function begins around 20 years earlier, when women reach around the age of 30 [3].

Age-dependent differences in ovaries

In this new study, the researcher focused on exploring human ovaries and the changes to their gene expression (the transcriptome) with age.

One of the biggest challenges to understanding changes in gene expression in human ovarian aging is obtaining tissues for studies. However, these researchers were able to obtain the ovaries of 15 volunteers who donated them following surgery. Those were divided into three groups based on age: young (18-28 years), middle-aged (36-39 years), and older (47-49 years).

Human ovaries are organs that are built from different types of cells [4]. Each cell type has different characteristics and expresses different genes. To understand the aging processes of these different cell types, the authors used techniques that measure gene expression at the single-cell level and compare the gene expression between different age groups and cell types [5].

While there were many differences between each cell type, the gene expression analysis generally revealed “significant differences between perimenopausal ovaries and those with reproductive function in young or middle-aged stage.” A more detailed analysis points to cellular senescence as an important player in ovarian aging. The authors also highlight features such as the senescence-associated secretory phenotype (SASP), increased cellular aging hallmarks in aged ovaries, such as SA-β-gal activity and lipofuscin accumulation, and oxidative protein damage.

The SASP molecules secreted by senescent cells are known to lead to inflammation [6]. Those previously observed connections were also observed in this research, as the researchers observed increased levels of inflammation-related molecules. An increase in inflammation and SASP molecules can lead to the spreading of the senescent phenotype and oocyte damage, which was supported by the observation that DNA damage systems were also activated in aged oocytes.

FOXP1, the crucial regulator

After analyzing the common molecular processes and gene expression in different types of ovarian cells, the researchers looked for the transcription factor regulating these processes. They identified “FOXP1 as a crucial TF regulating cellular senescence in the ovary” and observed that aging decreased FOXP1 levels.

They also tested FOXP1 in mice. The depletion of FOXP1 in granulosa cells led to expedited ovarian aging, senescence-associated changes in gene expression patterns, increased levels of senescent markers, and more granulosa cells dying by apoptosis. However, they noted this experiment’s limitations, as knocking down FOXP1 in mice cannot fully replicate human ovarian aging.

Quercetin’s anti-aging effect

The authors went a step further and tested potential anti-aging drugs and their effects on the ovarian reserve in middle-aged mice and human ovarian granulosa tumor cell lines. They tested fisetin, quercetin, and dasatinib, which are already known to have anti-aging properties [7]. First, testing in human cell lines showed that quercetin and fisetin “delayed FOXP1 gene silencing-induced cellular senescence,” improved cell proliferation, and decreased levels of a DNA damage marker. Quercetin also activated FOXP1 expression, suggesting that it can inhibit senescence.

Those promising results prompted researchers to test quercetin in reproductively aged (36-week-old and 48-week-old) mice. These ages correspond roughly to 38-40 and 48-50 in humans. Mice received one month of quercetin treatment without any side effects. Follow-up testing showed improvements in the ovarian reserves of 36-week-old, but not 48-week-old, mice.

Additionally, quercetin-treated 36-week-old mice were able to carry more successful pregnancies compared to the control group. The lack of improvement observed in the 48-week-old mice is probably due to the limited number of follicles, the sacs that contain immature eggs, in those old mice.

Overall, this study contributed to a better understanding of female aging processes. The comprehensive analysis conducted by the authors allowed them to create “single-cell and spatial transcriptomic maps of human ovaries across different age groups.” These maps allowed for examining gene expression changes and differences in eight types of human ovarian cells.

Our study deepens the understanding of human ovarian aging, providing a valuable resource for investigating potential therapeutic interventions. Moving forward, we aim to explore FOXP1 as a potential target for both the diagnosis and treatment of human ovarian aging.

Literature

[1] Wu, M., Tang, W., Chen, Y., Xue, L., Dai, J., Li, Y., Zhu, X., Wu, C., Xiong, J., Zhang, J., Wu, T., Zhou, S., Chen, D., Sun, C., Yu, J., Li, H., Guo, Y., Huang, Y., Zhu, Q., Wei, S., … Wang, S. (2024). Spatiotemporal transcriptomic changes of human ovarian aging and the regulatory role of FOXP1. Nature aging, 10.1038/s43587-024-00607-1. Advance online publication.

[2] Baerwald, A. R., Adams, G. P., & Pierson, R. A. (2012). Ovarian antral folliculogenesis during the human menstrual cycle: a review. Human reproduction update, 18(1), 73–91.

[3] Broekmans, F. J., Knauff, E. A., te Velde, E. R., Macklon, N. S., & Fauser, B. C. (2007). Female reproductive ageing: current knowledge and future trends. Trends in endocrinology and metabolism: TEM, 18(2), 58–65.

[4] Hsueh, A. J., Kawamura, K., Cheng, Y., & Fauser, B. C. (2015). Intraovarian control of early folliculogenesis. Endocrine reviews, 36(1), 1–24.

[5] Tabula Muris Consortium (2020). A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature, 583(7817), 590–595.

[6] Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews. Molecular cell biology, 15(7), 482–496.

[7] Di Micco, R., Krizhanovsky, V., Baker, D., & d’Adda di Fagagna, F. (2021). Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nature reviews. Molecular cell biology, 22(2), 75–95.

SynBioBeta, the leading community of entrepreneurs, investors, innovators, and biological engineers, today announced details for its flagship SynBioBeta 2024 conference. The premier annual event for the synthetic biology industry will be held May 6-9, 2024, in San Jose, gathering an estimated 2,000 attendees from around the world.

“Synthetic biology is rapidly transforming nearly every sector of our economy and society in profound ways,” said John Cumbers, founder of SynBioBeta. “Our annual conference brings together the world’s preeminent minds and companies driving innovation in this space to tackle humanity’s greatest challenges in health, sustainability, materials, and our fundamental understanding of life itself.”

SynBioBeta 2024 will feature over 180 content sessions across 18 tracks focused on the most critical frontiers in synthetic biology, including engineered human therapies, longevity, psychedelics, AI and digital biology, climate solutions, food and agriculture, chemicals and materials, biosecurity and more. A renowned line-up of over 200 speakers will take the stage, headlined by keynotes from Stephen Wolfram of Wolfram Research, Stephen Quake of the Chan Zuckerberg Initiative, investor Vinod Khosla of Khosla Ventures, genomics pioneer Craig Venter, mushroom expert Paul Stamets, biotech entrepreneur Martine Rothblatt, and Valerie Sarisky-Reed from the US Government’s Department of Energy.

“Taking the SynBioBeta stage is an unmatched opportunity to share our work with the people who truly comprehend its enormity,” said Jodi Barrientos, Chief Executive Officer at Ribbon Biolabs.” The audience is highly engaged, fostering stimulating discussions that have the potential to influence various fields such as medicine, materials science, and climate solutions. It is the ultimate gathering for those at the forefront of the synthetic biology revolution.”

The global synthetic biology market was valued at $6.3 billion in 2021 and is projected to grow at a staggering CAGR of around 25% to reach $38.7 billion by 2030 (Markets&Markets).

Key drivers include increasing demand for synthetic biology products in healthcare, industrial applications, food and agriculture, and rising investments.

In addition to the extensive conference programming, SynBioBeta 2024 will host over 200 exhibitors and sponsors showcasing the latest synthetic biology tools, technologies and applications. Exhibitors range from industry leaders like Ginkgo Bioworks and DNA Script to cutting-edge startups such as Asimov, Molecular Assemblies, and Ansa Biotechnologies.

“SynBioBeta is a mind-expanding experience that renews your sense of awe about the transformative potential of synthetic biology,” said Richard Kitney, Professor of Biomedical Systems Engineering and Co-Director of the UK’s National Industrial Translation Centre for Synthetic Biology at Imperial College London. “The cross-pollination of ideas, the windows into cutting-edge research, the ability to connect with the pioneers reimagining what’s possible with biology – it all conveys a future vision that is incredibly inspiring. You leave reinvigorated about this field’s power to solve humanity’s greatest challenges.”

A major highlight will be the SynBioBeta Global Synthetic Biology Awards ceremony recognizing standout achievement and impact across categories like Lifetime Achievement, Pioneer Award, Industry Leader Award, and Rising Star Award.

To register or apply to exhibit, speak, or sponsor at SynBioBeta 2024, please visit SynBioBeta 2024.

Media Relations:

Katie Orrell, Director of Marketing

katie.orrell@synbiobeta.com

About SynBioBeta

SynBioBeta is the premier innovation network for biological engineers, investors, innovators, and entrepreneurs who share a passion for using biology to build a better, more sustainable world. We provide our community members with personal and professional development support, as well as valuable opportunities for partnership, collaboration, networking, and education. We host The Global Synthetic Biology Conference each year, which highlights the innovative developments in synthetic biology that are transforming how we fuel, heal, and feed the world. Our Weekly Newsletter provides opportunities to highlight our partners research, thoughts, and discoveries while telling the story of the bioeconomy.

The longevity company Gero has presented its new nonprofit initiative: a series of studies using the company’s aging clock, which is based on stepping patterns obtained from phones and wearables.

One small step for man, one giant leap for aging research?

Gero, an AI longevity company, has announced a new non-profit initiative named GeroSense Studies. GeroSense is its division dedicated to developing digital biomarkers of aging using data from smartphones and wearable devices.

In a recent industry survey conducted by the Longevity Biotech Fellowship, dozens of experts named the lack of validated biomarkers of aging as the number one bottleneck in the field. While other researchers try to deduce biological age and the rate of aging from epigenetic alterations and blood metabolome, GeroSense chose an uncommon approach. Its model uses only step patterns and, optionally, heart rate. Trained on data from UK Biobank and the NHANES study, it is roughly as precise – at least, according to Gero – as the well-regarded second-generation epigenetic clock PhenoAge.

The model’s predictive power surprised even its creators. According to Gero CEO Peter Fedichev, it goes beyond a simple linear relationship between the average daily number of steps and aging. For instance, the model correctly adjusts the results by occupation: that is, it knows that people who have to do a lot of walking for work, such as waiters or construction workers, tend to age faster on average than middle-class managers who might clock fewer steps but, overall, lead healthier lifestyles.

In an X thread announcing GeroSense Studies, Aleksandr Sviridov, CTO of Gero, noted: “You can spot the difference between 20, 50, and 80-year-olds just by looking at how they walk because how we move encapsulates almost every aspect of our health.” Fedichev likens this to studying exploratory behavior in mice, which can tell a lot about their health and aging. You can’t put humans in cages to constantly monitor their activity, but step patterns might be a good enough proxy.

The importance of human data

GeroSense has an app that anyone with an iPhone can download and start obsessively watching their daily fluctuations in biological age. The Android version is currently in the works, but you can join the waiting list.

A screenshot from the GeroSense app

The new initiative means that GeroSense will start using this platform for studies on how various factors and interventions move the hands of the step-based aging clock. The first proof-of-concept study will involve a lot of self-reporting: a monthly lifestyle survey in which participants will be asked about their dietary habits as well as about the supplements and medications they are taking. Additionally, they will complete two bi-weekly clinically verified assessments for anxiety and depression, both suspected to be important factors in aging.

“Hormesis and stress mimetics are tested in mice,” Peter said, “but mental health and social status is something you can’t measure in animal models, so their effect on aging is understudied.”

According to Aleksandr, with their pilot study, they hope to validate their model by detecting well-known signals, such as from smoking, and, ideally, identify some yet-unreported large-size effects. The data will be anonymized and made publicly available, although you can opt-out if you are not interested in advancing the science of longevity (please don’t). According to Gero, the new initiative is completely non-profit and represents the company’s attempt to benefit the entire field.

“We are not content with the situation where we haven’t found anything that prolongs lifespan more robustly than rapamycin,” Aleksandr explained. Peter, who has floated his own theory of aging (you can read all about it in our interview with him), maintains that mice age in a fundamentally different way than humans, which is why data from mouse studies isn’t very helpful in understanding human aging and how various interventions affect it.

Participation is crucial

Of course, studies like the ones that GeroSense plans to run have numerous limitations. For instance, there is no randomization, and self-reporting is notoriously unreliable. However, large sample sizes can mitigate some of the deficiencies, which is why GeroSense hopes to recruit many participants. With wearables still not widely popular, GeroSense’ obvious advantage is that it can gather basic data on steps from smartphones as long as participants remember to carry their phones.

Aleksandr is aware of those limitations but says that it’s quantity versus quality; GeroSense’s approach will potentially allow the testing of a variety of understudied factors and interventions. This is reminiscent of another initiative we recently covered: Ora Biomedical’s Million Molecule Challenge. While GeroSense insists on the importance of human data, MMC is about high-throughput testing in worms.

However, the unifying idea is that we must cast a wider net if we want to “unstick” the longevity field. In fact, Aleksandr says, GeroSense’s initiative was somewhat inspired by the self-reporting-based study of rapamycin co-authored by Ora’s co-founder Matt Kaeberlein. GeroSense plans to reproduce this study in the future.

GeroSense’s approach can prove especially valuable for investigating the anti-aging effects of supplements that do not get tested in high-quality studies a lot. Other targets that the company’s currently eyeing include fasting, antidepressants, microdosed psychedelics, and GLP-1 agonists such as Ozempic. However, it all hinges on participation.