Extremely Long Lived Proteins and Female Reproductive Aging

Project: Research project

Project Details

Description

The female reproductive system is a powerful model for studying aging mechanisms because it ages decades prior to other organs in the human body. Reproductive function begins to decline when women are only in their mid-30s and ceases completely at menopause. Female reproductive aging phenotypes include reduced endocrine function and decreased gamete quantity and quality. Together, these changes contribute to adverse fertility and general health outcomes, and such consequences are becoming more tangible as medical advances are extending lifespan and women worldwide are delaying childbearing. Several fundamental hallmarks of aging tissues have been identified including impaired protein homeostasis or proteostasis. Proteins are required for the structure and function of all tissues and are involved in critical cellular processes. As such, regulatory mechanisms are in place to ensure that proteins are synthesized, folded, and modified properly. As proteins age, however, they accumulate various types of damage, and damaged proteins are typically turned over and replaced with newly synthesized functional ones to maintain proteostasis. Most proteins only last a total of two days or less. However, a unique class of proteins called extremely long lived proteins (ELLPs) can last the entire lifetime of an organism without being replaced. ELLPs are typically part of large complexes (e.g. histones, nuclear pores, structural networks) and underpin aging because accumulated damage compromises their function and may also elicit abnormal signaling pathways. The pathogenic properties of ELLPs are particularly problematic in post-mitotic cells because they are not diluted through cell division. In fact, neuronal ELLPs are implicated in aging and neurodegenerative conditions. Like neurons, the mammalian oocyte is also vulnerable to ELLPs because it is non-dividing but rather maintained in an extended prophase I arrest for up to months in mouse and decades in human. Thus, dama
StatusFinished
Effective start/end date5/15/194/30/22

Funding

  • National Institute of Child Health and Human Development (5R21HD098498-02)

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