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Nucleoli Identified As Potential Markers Of Aging

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Female reproductive aging is a major issue in today’s modern society. More and more women are choosing to delay childbearing for reasons that vary from effective contraception, increased presence in the workforce, and changes in values and family structures.

However, the female reproductive system is the first to age in the human body, and it is characterized by a loss of gamete (oocyte) quantity and quality that begins already when women reach their mid-thirties. Reproductive aging can lead to infertility and can also have a broad impact on general health because of ovarian hormones, such as estrogen, drive cardiovascular, immune, cognitive, and bone functions. Moreover, as the gap between menopause and life expectancy is increasing due to health care advances, women will spend a large portion of their lives in a post-reproductive endocrine milieu. Thus, understanding the cellular and molecular mechanisms that underlie reproductive aging is a major frontier in women’s health research.

Female age-associated infertility is often due to defects that occur at the level of the gamete. This phenomenon is best exemplified by data from Assisted Reproductive Technologies (ART) such as in vitro fertilization. For example, when women use their own oocytes to conceive via ART procedures, the likelihood of having a live offspring following embryo transfer decreases with age.  In contrast, if women use oocytes from young, healthy donors to conceive, the maternal age effect is abrogated. Thus, the biological age of the oocyte dictates reproductive outcomes.

Analyzing Gene Expression Changes Associated With Advanced Reproductive Age

One important measure of oocyte quality is the mitochondrial function. Mitochondria generate the energy, in the form of ATP, that a cell needs to carry out cellular processes. Mitochondrial dysfunction is one of the most prominent cytoplasmic changes that occur with age in the oocyte. Although mitochondrial transplantation in oocytes has been performed in the context of IVF for mitochondrial disease, this technique is experimental and highly controversial.

To expand our knowledge of what goes wrong in the oocyte with advanced reproductive age, we used a mouse model of physiologic aging or simply put, old mice. Unbiased molecular methods identified gene expression changes associated with follicles from reproductively old and young mice. Not surprisingly, we identified signatures indicating mitochondria were affected with age. However, the big surprise was that a new organelle was implicated in aging, the nucleolus. The nucleolus is a subnuclear structure where ribosomes are made.

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Ribosomes are the molecular machines that synthesize all the proteins in a cell. Further experiments examining the nucleolus in oocytes confirmed that there are age-associated changes in the appearance and structure of this organelle. Strikingly, aging oocytes had more ribosomes compared to their younger counterparts. These results shift the current thinking about reproductive aging, providing the first indication that changes in nucleoli, ribosomes, and protein synthesis could be key factors in the age-related quality decline in oocytes.

These results are not unique to reproductive aging. In fact, two other recent reports published back to back in Nature Communications found intriguingly similar relationships between nucleoli and aging. Researchers at the Salk studying Hutchison-Gilford progeria, a rare disease associated with accelerated aging, found that nucleoli in cell models of this syndrome were enlarged and ribosome production was increased. Furthermore, expansion of nucleolar size and activity was also observed in healthy cells with age.  Another study found that, conversely, small nucleoli and decreased protein synthesis extended lifespan in roundworms and mice. Thus, overactive ribosome biogenesis and protein synthesis may be common features of the aging environment in reproductive aging, premature aging, and physiologic aging.

Together these findings highlight nucleoli as potential biomarkers of aging. Furthermore, nucleoli and ribosomes may be suitable targets for anti-aging therapies across multiple aging conditions.

This study Age-associated dysregulation of protein metabolism in the mammalian oocyte was recently published in the journal Aging Cell.

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About The Author

The female reproductive system is the first to age in the human body and will affect every single woman. Reproductive aging is characterized by a noticeable decline in egg quantity and quality beginning in women when they reach their mid-thirties and continuing until menopause. Female reproductive aging has significant health consequences as it results in endocrine function loss and is a leading cause of infertility, miscarriages, and birth defects. Reproductive aging has a large societal impact as women globally are delaying childbearing and many women of advanced reproductive age rely on Assisted Reproductive Technologies (ART) to conceive.

The Duncan Lab uses mammalian model systems (mouse, bovine, and human) to investigate the overarching hypothesis that deterioration of oocyte-intrinsic cellular pathways together with alterations in the ovarian environment underlie the age-associated decline in female gamete quantity and quality. Our research will improve the fertile-span and health-span across generations through discovery of novel cellular pathways for therapeutic interventions.

Chromosomes are the genetic material that encode the instructions for life. Chromosomes experience many processes during a single cell cycle such as replication, recombination, condensation and transcription. Many of the proteins and pathways that operate on chromosomes are evolutionarily conserved from budding yeast to man. Defects in chromosome function underlie many human diseases such as cancer and birth defects. My research program takes advantage of yeast and mammalian model systems and uses genomics, genetics, live microscopy, molecular biology, and biochemistry to study processes that contribute to chromosome function, in particular, 1) SMC complexes and 2) centromeric chromatin.