Oocyte aging, the mitochondrial downward spiral, and the path to responsible innovation

Le résumé fourni par la source

As Human Reproduction celebrates its 40th anniversary in 2026, the journal has curated a series of commentaries to reflect on the landmark papers that have shaped each decade of our field. For the 2020s, the selection of our 2023 paper, ‘Human ovarian aging is characterized by oxidative damage and mitochondrial dysfunction’, is of great honor to our team (Smits et al., 2023). In this contribution, we reflect on the outcomes of this work and how these findings should find their way to patients in the current field of reproductive medicine, identifying critical gaps that must be bridged to improve the effectiveness and safety of our treatments. The tension between our advancing molecular understanding of oocyte aging and the profound gaps in our basic in vitro culture knowledge highlights the critical need for transparent, evidence-based innovation in an increasingly commercialized field. Our study provided direct evidence in human follicles that hallmarks of aging, such as oxidative damage and mitochondrial dysfunction, are present before an oocyte reaches maturity. Traditionally, oocyte aging was often viewed through the lens of late-stage failures, such as spindle defects or aneuploidy in the oocyte. However, by utilizing formalin-fixed paraffin-embedded ovarian tissue and super-resolution immunofluorescence microscopy, we demonstrated that part of the ‘aging’ of the oocyte is a lifelong progressive process that begins as early as the primordial follicle stage. We observed an age-dependent accumulation of oxidative damage to proteins and lipids within quiescent follicles, indicating that oxidative stress may already start compromising the oocyte’s structural and functional integrity potentially decades before a patient typically seeks fertility treatment. Detailed metabolomic mapping subsequently revealed an accumulation of glycolytic substrates and glutamine, alongside a profound depletion of nicotinamide adenine dinucleotide (NAD+) and essential monophosphate nucleotides. This suggests that while mitochondria remain active and attempt to function, the tricarboxylic acid cycle becomes unable to process all available substrates. NAD+ depletion can induce a ‘downward spiral’: less NAD+ can lead to decreased mitochondrial biogenesis, which further exacerbates oxidative stress, lipid peroxidation, and widespread protein damage. While the surrounding granulosa or cumulus cells appear to mount a compensatory response, perhaps by increasing ATP levels in the affected oocyte through gap-junctional transfer, this intricate metabolic synergy is ultimately fragile and insufficient to halt the decline. These findings carry profound clinical implications. Women of advanced maternal age represent an increasingly large proportion of the IVF population, yet IVF remains essentially powerless against advancing oocyte age. Currently, IVF does not ‘cure’ or reverse aging; it merely attempts to retrieve what viable reproductive potential is left. Our results explain exactly why IVF fails to overcome this age barrier: the structural and metabolic deterioration—specifically the irreversible oxidative damage and the mitochondrial dysfunction characterized by an impaired NAD+ biosynthesis pathway—is already cemented deep within the oocytes. Because the foundational bioenergetic machinery of these oocytes is fundamentally compromised before ovulation, simply extracting them and placing them in standard culture media cannot correct the intracellular damage. The oocyte needs fully functional mitochondria to execute the extraordinarily demanding tasks of maturation, fertilization, and embryonic development. The concept that human ovarian aging is driven by this mitochondrial downward spiral results in the tantalizing prospect of ‘oocyte rejuvenation’. If the depletion of NAD+ and its precursors is a central feature of the aging oocyte, the logical question arises: can we reverse the biological clock? Recent literature has already provided compelling evidence regarding the metabolic rejuvenation potential of NAD+ precursors, outlining how targeted metabolic interventions might restore mitochondrial function and improve oocyte competence in aging models (Bertoldo et al., 2020). These findings have sparked excitement, suggesting that what was once considered an inevitable biological decline might be therapeutically modifiable. However, this potential brings us to a critical and perilous junction in our field. The clinical appetite for new treatments in our field is well known, often driving the premature adoption of interventions before safety and efficacy are fully established. This clinical ‘thirst’ was vividly illustrated after our keynote lecture at the European Society of Human Reproduction and Embryology (ESHRE) 2025 annual meeting, where we presented this work. Despite repeated disclaimers during the presentation regarding the extensive pre-clinical validation still required, the very first question from an audience member after the session was simply, ‘Ok, very interesting, but how much should I inject into my patients?’ This rush highlights a recurring and dangerous problem in reproductive medicine: the temptation to translate preliminary laboratory findings into routine clinical practice driven by hope, desperation, and commercialism. The leap from animal models and early-stage metabolic data to patient administration without rigorous dose-finding studies ignores the fundamental principles of pharmacology. While an optimal concentration of an NAD+ precursor might theoretically enhance culture conditions or systemic environments, suboptimal doses will be inefficient, while excessive doses could prove to have reverse effects or even be toxic (Guo et al., 2022; Di Emidio et al., 2024). Lots of research is simply still needed. Furthermore, we must recognize that the scientific foundation for many of the things we do is simply unknown or still very limited. This is nowhere more apparent than in the proprietary ‘secrecy’ of commercial embryo culture media. We cannot hope to optimize, let alone rejuvenate, oocytes in vitro if we do not know the foundational composition of our culture systems. A powerful analogy used by Hans Evers, former Editor-in-Chief of Human Reproduction, previously highlighted this ethical and scientific crisis: in his Editorial, he wrote that he likes peanut butter, and that one can read on the back of every jar of peanut butter its exact composition. He then rightfully questioned the practice that we accept less for the medical devices and the embryo culture media that shape the future health of a child (Hans Evers, 2016). This call for transparency is driven by the understanding that transparency is needed to improve the effectiveness and safety of what we do (Sunde et al., 2016; Paulson and Adashi, 2024). It is not unlikely that even subtle variations in culture media can induce significant epigenetic alterations, linking back to the Barker hypothesis of fetal origins of adult disease. Pre-clinical and clinical data support this notion of long-term impact of IVF culture media and culture conditions on offspring, possibly driven by epigenetic interactions (Banrezes et al., 2011;Kleijkers et al., 2016; Velazquez et al., 2018). We have to consider the long-term biological consequences of our laboratory choices. Even more striking is that it has been shown that the foundations of our commercial media are built on shockingly sparse evidence, often relying on outdated animal studies and a handful of human measurements that fail to reflect actual in vivo physiological conditions. As an example, when we analyzed all commercially available embryo culture media used in IVF, we found that all sequential media used high glucose concentrations in fertilization media, low glucose concentrations in cleavage stage media, and high glucose concentrations in blastocyst stages of preimplantation embryo development (Zagers et al., 2025). The evidence this seems to be or

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