# Sequestration and clearance of age-induced damage in gametogenesis

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $40,834

## Abstract

Organisms acquire damage as they age1, 2. Common traits that are associated in aged cells are the
accumulation of protein aggregates, nucleolar abnormalities and dysfunctional organelles2, 3,5. However, it
remains difficult to distinguish which traits directly promote cellular aging, versus those that arise as a
consequence of aging. Generating a model system that addresses this issue will allow us to develop better
therapeutic strategies to combat aging and improve health span.
 Similar to metazoans, budding yeast accumulates protein aggregates, nucleolar abnormalities and
dysfunctional organelles during aging. Surprisingly, as aged yeast cells undergo gametogenesis, the resulting
gametes no longer contain the age-associated traits6. Furthermore, the longevity of the gametes is restored by
this process, suggesting that elimination of age-associated traits causes cellular rejuvenation6. I aim to dissect
the molecular mechanisms that counteract age-induced damage during gametogenesis and test their impact
on lifespan.
 The experiments in Aim 1 will determine which genes in budding yeast cause gametes to avoid the
inheritance of age-associated traits. Analyses so far indicate that cellular contents subject to age-induced
damage, including nuclear pore complexes, protein aggregates and the nucleoli, localize to a subcompartment
of the nuclear envelope during gametogenesis. This compartment is not inherited by the gametes as they
regenerate contents de novo 8, 12. These observations suggest that age-induced traits are associated with the
nuclear envelope subcompartment via specific adaptors, which cause their exclusion from the gametes. If true,
disruption of each candidate adaptor should lead to retention of a distinct type of age-induced damage. In
parallel, an unbiased genetic approach will be taken to screen for mutants that pass on age-induced traits to
their gametes30. Further assessment of each mutant by microfluidic pedigree analyses will reveal which traits
are limiting for lifespan39.
 The experiments in Aim 2 will determine how long-lived proteins that accumulate in aged cells are
destroyed during budding yeast and C.elegans gametogenesis. Budding yeast gametes do not inherit the
vacuole of the progenitor cell, which is ultimately destroyed. When the vacuole lyses, it releases proteases that
normally degrade long-lived proteins7, 13, 14. Therefore, inhibiting vacuolar proteases, as well as other factors
associated with protein quality control may cause long-lived proteins found in aged cells to persist during
gametogenesis. Similar phenomena have been recently reported in the C.elegans germline, which will
additionally be explored17, 18. The results will be verified by yeast genetics, worm genetics and fluorescence
live-cell imaging. Identifying the genes required to eliminate long-lived proteins will facilitate the generation of
new strategies to remove proteotoxic damage.

## Key facts

- **NIH application ID:** 9941035
- **Project number:** 5F31AG060656-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Jay S Goodman
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $40,834
- **Award type:** 5
- **Project period:** 2018-07-20 → 2021-07-19

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9941035

## Citation

> US National Institutes of Health, RePORTER application 9941035, Sequestration and clearance of age-induced damage in gametogenesis (5F31AG060656-03). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9941035. Licensed CC0.

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