Most proteins in the body are continually replaced on a fairly short time frame, either because replacement takes place inside cells, or because the cells themselves are replaced over time. In the few lasting cell populations, such as neurons in the brain and oocytes in the ovaries, there is the potential for cells and even individual protein molecules in those cells to have a life span that is as long as the overall life span of the animal or person. This is a point of concern because large molecules in the cell can become chemically altered in harmful ways over time, negatively affecting cell function. At the present time, it is far from clear as to how best to approach this problem, and how much of a contribution to age-related loss of function it provides.
In today's open access paper, researchers characterize long-lived proteins in oocytes and the surrounding ovary structures. This characterization doesn't demonstrate that the presence of long-lived proteins, and thus loss of function due to damaging chemical alterations, is a major contributing cause of dysfunction. But is is strongly suggestive that there will be some contribution to loss of function. Unlike the brain, another location of long-lived proteins, the ovaries age into loss of function comparatively early in life. Are long-lived proteins meaningful in this early aging, or is it other factors? That question remains to be answered.
The female reproductive system is the first to age in the human body with fertility decreasing for women in their mid-thirties and reproductive function ceasing completely at menopause. In the ovary, aging is associated with a loss in gamete quantity and quality which contributes to infertility, miscarriages, and birth defects. Moreover, the age-dependent loss of the ovarian hormone, estrogen, has adverse general health outcomes. These sequelae are significant as women globally are delaying childbearing and the gap between menopause and lifespan is widening due to medical interventions.
Although aging is a multifaceted process, loss of proteostasis and dysfunctional protein quality control pathways are hallmarks of reproductive aging. The mammalian ovary is comprised of a fixed and nonrenewable pool of long-lived cells or oocytes. In humans, oocytes initiate meiosis during fetal development, and by birth, all oocytes are arrested in the cell cycle. This cell cycle arrest is maintained until ovulation, which occurs any time between puberty and menopause, and thus can span decades. The oocytes are particularly sensitive to protein metabolism alterations because they contribute the bulk cytoplasm to the embryo following fertilization. Thus, maternal proteins produced during oogenesis are essential to generate high-quality gametes.
The ovarian microenvironment is a critical determinant of gamete quality and has been shown to become fibro-inflamed and stiff with age. Although a small number of oocyte-specific proteins have been identified as long-lived, including cohesins and several centromere-specific histones, there has not been a discovery-based approach to define the long-lived proteome of the ovary and oocyte. Thus, the potential contribution of long-lived proteins (LLPs) to the age-related deterioration of the reproductive system in mammals remains to be elucidated. In this study we used multi-generational whole animal metabolic stable isotope labeling and leading mass spectrometry (MS)-based quantitative proteomic approaches to visualize and identify ovarian and oocyte long-lived macromolecules in vivo during milestones relevant to the reproductive system.
LLPs tend to be part of large protein complexes and include histones, nuclear pore complex proteins, lamins, myelin proteins, and mitochondrial proteins. In the ovary, the major categories of LLPs included histones, cytoskeletal proteins, and mitochondrial proteins. Our findings provide a novel framework for how long-lived structures may regulate gamete quality. Long-lived macromolecules localized throughout the ovary including the follicular compartment with prominent signals in the granulosa cells of primordial and primary follicles relative to later stage growing follicles. These findings are consistent with the knowledge that the squamous pre-granulosa cells surrounding the oocyte within primordial follicles form early in development. These squamous granulosa cells are generally thought to lack the ability to undergo mitotic division until follicles are activated to grow, so it is not surprising that we observed long-lived macromolecules persisting within them. Thus, it is possible that these long-lived molecules will accumulate more damage in primordial follicles that remain quiescent for longer periods relative to those that activate earlier. Whether such damage occurs and how it translates into decreased follicle survival or gamete quality will require further investigation.
Within the extrafollicular ovarian environment, the ovarian surface epithelium (OSE) exhibited a striking enrichment of long-lived molecules. The OSE is highly dynamic due to repeated post-ovulation wound healing and repair, and its regenerative capacity occurs through a somatic stem/progenitor cell-mediated process. Interestingly, LLPs are retained in other cells undergoing repeated asymmetric divisions and are speculated to contribute to the reproductive aging process. Consistent with this possibility, the architecture and wound healing ability of the OSE is altered with advanced reproductive age.
View the full article at FightAging
