# Extremely Long Lived Proteins and Female Reproductive Aging

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2020 · $203,800

## Abstract

The female reproductive system is an instructive 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 essential 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 versions to maintain proteostasis. Most proteins last only 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 ELLP dysfunction 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, damaged ELLPs could accumulate, reduce gamete quality, and
may even be passed onto the next generation through the embryo. While ELLPs provide a compelling
intellectual framework for considering mechanisms of female reproductive aging, their identification and
quantification at the single protein level has been historically challenging due to technical limitations especially
within limited biological material. Here we propose to combine a two generation whole animal stable pulse-
chase isotope labelling approach with advanced mass spectrometry-based approaches to identify and quantify
the extremely long lived proteome in the ovary and oocyte (Aim 1) and to image and quantitatively analyze long
lived molecules (proteins, lipids, nucleotides) in the oocyte and ovary within the context of the in vivo
microenvironment (Aim 2). These experiments will be performed at two time points across the reproductive aging
continuum and encompass the necessary pioneering steps to identify specifi...

## Key facts

- **NIH application ID:** 9929620
- **Project number:** 5R21HD098498-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Francesca E. Duncan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $203,800
- **Award type:** 5
- **Project period:** 2019-05-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929620

## Citation

> US National Institutes of Health, RePORTER application 9929620, Extremely Long Lived Proteins and Female Reproductive Aging (5R21HD098498-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9929620. Licensed CC0.

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