On October 16, 2023, a groundbreaking study by Professor Xiong Bo and his team at Nanjing Agricultural University was featured in Nature Aging. The study, titled “Polyamine metabolite spermidine rejuvenates oocyte quality by enhancing mitophagy during female reproductive aging,” reveals the critical role of spermidine in reversing age-related decline in oocyte quality and ovarian function.
This innovative research shows that decreased spermidine levels within the ovaries are linked to diminished oocyte quality during aging. The team successfully improved mitochondrial autophagy by supplementing spermidine, enhancing oocyte quality and fertility in aging female mice. This research has significant implications for therapeutic strategies to extend reproductive health and lifespan in mammals, with potential applications to human fertility treatments.
Spermidine, a polyamine metabolite initially identified in semen and named for its origin, pervades various biological organisms, extending its presence to human tissues, including the ovaries. Recent research highlights spermidine’s extraordinary anti-aging properties, suggesting it could combat declining ovarian function and fertility associated with aging. Despite these promising findings, the specific effects of spermidine on the reproductive system of aging female animals and the underlying mechanisms await detailed exploration. This gap in knowledge presents an exciting frontier for scientific inquiry into natural compounds that may hold the key to enhancing reproductive longevity.
In an interview with Cima Science, Professor Xiong Bo’s research illuminated a crucial discovery. Metabolomic studies indicated a significant reduction in spermidine within the ovaries of older mice compared to their younger counterparts. This correlates with diminished oocyte quality and additional indicators of ovarian aging. Prompted by these findings, Professor Xiong Bo posed critical questions: Could a shortfall in spermidine be a key factor in the declining oocyte quality observed in aging mice? And, would spermidine supplementation enhance oocyte quality and fertility in these older mice? These inquiries pave the way for potential interventions to support reproductive health as females age.
Metabolomic analysis of the ovaries of aging mice shows a decline in spermidine levels in their ovaries.
In a groundbreaking study, researchers sought to establish a direct link between spermidine levels and fertility in female mice. The team’s method of supplying aging mice with spermidine through injections led to significant follicle count and quality enhancements. This was especially true for antral and preantral follicles, key markers for assessing ovarian reserves in human fertility evaluations. Remarkably, the reversal of oocyte aging was achievable even when spermidine was simply added to the drinking water.
The increase in spermidine levels was instrumental in boosting follicular growth, advancing oocyte maturity, and improving in vitro fertilization success and early embryonic development potential. One of the most striking outcomes was that spermidine supplementation nearly doubled the number of offspring produced by the aging female mice, offering promising insights for fertility research.
The impact of spermidine supplementation on the fertilization capacity of oocytes and the potential for embryo development in aging mice.
In a compelling extension of their work, Professor Xiong Bo’s research team found that spermidine’s beneficial effects on oocytes are not limited to mice but also manifest in aging pig oocytes cultured in the lab. This cross-species consistency hints at a universal action mechanism for spermidine’s anti-aging influence on reproductive cells. Despite prior knowledge of spermidine’s anti-aging properties, its profound impact on oocytes remains an exciting revelation.
Delving into the molecular underpinnings, the researchers discovered a decline in autophagy processes, specifically mitophagy, within aging oocytes. Spermidine supplementation seemed to counteract this decline, reinstating mitophagy and enhancing mitochondrial quality—a conclusion drawn from the increase in mitochondrial membrane potential. The critical role of mitophagy was further underscored when its pharmacological inhibition negated the positive outcomes of spermidine, solidifying the connection between mitophagy and spermidine’s restorative effects.
The impact of spermidine supplementation on mitochondrial autophagy activity in oocytes of aging mice.
On August 4, 2020, Professor Xiong Bo’s research team made significant strides in fertility science with a paper in Cell Reports detailing how NMN, a precursor metabolite of NAD+, reinstates NAD+ levels and boosts mitochondrial functions in aging animal oocytes. This restoration process was linked to improved rates of oocyte meiotic maturation, fertilization, and embryo development potential, increasing animal offspring.
Professor Xiong Bo highlighted that while NMN and spermidine both rejuvenate aging animals’ reproductive capabilities by targeting mitochondria, they operate through distinct mechanisms. The possibility of a combined effect of these substances remains an intriguing prospect for future investigation.
The cutting-edge research in Nature Aging underscores spermidine’s vital importance in sustaining fertility in aging female mice, emphasizing that enhancing spermidine can reverse mitochondrial autophagy decline associated with aging oocytes. These breakthroughs not only provide insights into combating age-related reproductive decline but also open novel avenues for extending female reproductive health and addressing urgent fertility issues in humans.
Research model diagram: The decline in spermidine levels is a key factor in the loss of reproductive capacity associated with aging.
Professor Xiong Bo emphasized the critical nature of spermidine concentration in mouse studies, noting that insufficient and excessive levels can compromise oocyte quality. Therefore, before considering spermidine for extending the human reproductive lifespan, it is imperative to explore the optimal dosage and duration of supplementation to further establish its safety and effectiveness. The team’s upcoming focus involves assessing spermidine’s potential to enhance fertility in human oocytes through laboratory experiments.
Furthermore, ongoing human clinical trials are investigating spermidine supplementation for various purposes, including treating hypertension (NCT04405388), depression (NCT04823806), immune system aging (NCT05421546), and oral mucositis (NCT05926557). As more individuals seek medical support for conception, clinical trials exploring the potential of spermidine supplementation appear to be a promising avenue for research and application.
Simultaneously, Nature Aging published a “News & Views” article titled “Spermidine promotes fertility in aged female mice” by Frank Madeo and colleagues from the University of Graz in Austria.
Nature also published a news article titled “Anti-ageing molecule boosts fertility in aging mice,” highlighting this “undeniably groundbreaking” research, demonstrating that dietary supplements can reverse the decline in oocyte quality in aging mice.
- Zhang, Y., Bai, J., Cui, Z. et al. Polyamine metabolite spermidine rejuvenates oocyte quality by enhancing mitophagy during female reproductive aging. Nat Aging 3, 1372–1386 (2023). https://doi.org/10.1038/s43587-023-00498-8
- Conroy G. Anti-ageing molecule boosts fertility in ageing mice. Nature. 2023 Oct 16. doi: 10.1038/d41586-023-03224-x. Epub ahead of print. PMID: 37845477.