What keeps eggs in good shape as women age

What keeps human oocytes in good shape as women age

By David F. Albertini, PhD, Editor-in-Chief of the Journal of Assisted Reproduction and Genetics (JARG); Professor, Bedford Research Foundation, MA; Visiting Senior Scientist at The Center for Human Reproduction, NY; and Visiting Researcher at Rockefeller University, NY.

BRIEFING: As women are, likely, born with all their oocytes (eggs), it is reasonable to assume that oocytes—like somatic cells—are subject to aging, as they sit there in ovaries subcapsular in the midst of highly primitive so-called primordial follicles, waiting to be recruited into folliculogenesis. In this article the author offers a state-of-the-art update on our now greatly improved understanding of oocyte aging.

Female gametes, called oocytes, are precious commodities with an unusual history and an even more remarkable stage presence. For humans, as is the case for mammals in general, oocytes present special challenges due to unique properties they exhibit in sharp contrast to sperm or any other somatic cells of the body. For one thing, no other cell persists in a dormant or primordial state for as long as oocytes do. While most oocytes stored in ovarian primordial follicles will never reach the stage of development and maturation capable of yielding a viable embryo following fertilization, those that do undergo long periods of dormancy before initiating growth and differentiation within a follicle that will ultimately undergo ovulation.

As a result of their long-term storage, oocytes become subject to the wear and tear of progressive and unstoppable somatic aging, a condition that takes its toll on those oocytes that have been stored over the long haul. Among the properties most likely impacted with respect to the impact of aging on oocyte quality, meiosis and the genetic consequences of aberrant spindle function and errors in chromosome segregation have dominated in the literature. But sustaining the oocyte in a suspended state of animation in its primordial form or realizing the events that guarantee successful growth and final maturation, emerges as a complicated matter as to how the process of oogenesis manages to keep this remarkable cells’ house in order over the course of our reproductive lifespan. 

A new study from the laboratory of Melina Schuh, PhD, at the Max Planck Institute for Multidisciplinary Sciences in Germany, prompts us to think differently when it comes to sustaining the female germ cell pool over the course of time. Using a well-balanced and innovative set of investigational tools, asking the question of oocyte housekeeping in a new way Harasimov et al., turn attention away from the genome and towards the proteome as a sentinel for why and how to achieve the unique demands of longevity for the mammalian oocyte. 2 As with many frontline research efforts, this work challenges paradigms of the past and may in fact give substance to some of the more puzzling and perplexing aspects of oocyte aging implicit to current approaches for the treatment of human infertility. More on the topic of the oocyte proteome later!

That human oocytes demonstrate risky behaviors when it comes to reinitiating and completing meiosis has been recognized for years with the attendant focus on changes in recombination and spindle complexities offering insights into the maternal aging conundrum. 3 Much has been made of the oocyte aneuploidy problem across the age spectrum of humans with contemporary research efforts identifying many of the unusual properties of the specific proteins (and their timely post-translational modifications) drawn upon during chromosome alignment and segregation. 4-7 Drilling down on the proteomic players that orchestrate the meiotic dance of the chromosomes has until recently posed barriers to obtaining mechanistic insights that could guide and inform both research direction and clinical applications for the future. Herein lies the breakthroughs on proteomics in maternal aging.

Taking a variety of approaches that combine some human materials and an abundance of subject matter using the experimentally tractable mouse models, several laboratories are expanding our knowledge base on just what the oocyte stores, and in what form, beyond the traditional model of organelles and stored mRNAs and proteins that would be inherited by the zygote upon fertilization.2,8,9 While much of the “housekeeping stuffs” like mitochondria, Golgi complexes, and an endo-lysosome system have been known for years, 1 the demonstration of protein complexes of various kinds as both membrane-less condensates and lattices are now being viewed not only as reserves for future biosynthetic necessities during oocyte growth, maturation and post-fertilization events but as uniquely ling-lived assemblies subject directly, or indirectly, to the cumulative vagaries of advanced maternal aging. Notably, the extreme lifespan extending tendencies for proteins of oocytes are not unique to the oocyte itself but seem to be associated with the “house” withing which the oocyte lives, thrives, and potentially dies, -the all-important follicle in the ovary. 2

In a way, this line of thinking recapitulates a notion deeply embedded in the comparative biology of oogenesis having to do with the role of yolk as the nutritional substrate upon which most animals rely to support their post-fertilization development. 10 And not to short change how important the regulation of protein stores is to the many aspects of oocyte maturation and early development that have been linked genetically to arrested maturation or zygotic development, the substance of the maternal dowry is becoming appreciated for much more than contributions to the meiotic and mitotic spindle and the establishment of cytoplasmic-nuclear exchange at the all moments of zygotic gene activation.11, 12 Karyopherins are but one of many proteins now understood to perform essential functions in the embryo and having their origins during the growth and maturation of mammalian oocytes.13 And not only their biosynthesis and micromanagement over the lengthy lifespan of the oocyte are matters to be contended with, but the protein-based devices that constitute the Maternal Subcortical Complex (SCMC) are likely to be subject to some of the same rigorous controls exerted through proteostasis determining, in the end, which zygotes sustain term development and which do not.14

The final road to building and sustaining a good egg is long and punctuated by events and processes over a chronology that plays out over months in humans and weeks in a mouse. But the lifespan of an ovarian primordial oocyte is a lifetime, at least in terms of the years intervening menarche and menopause. Keeping the “egg house” in order thus becomes one of the great challenges in a society increasingly reliant upon Assisted Reproductive Technologies to manage and effect their family planning desires. The time has come to position the proteome and protein longevity on the basic science and clinical map for the future, something being enabled by the introduction of new experimental models of human ovary function. 15

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