# Multidimensional mapping of proteome changes and mechanisms underlying yeast replicative aging

> **NIH NIH R01** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2022 · $607,996

## Abstract

PROJECT SUMMARY
One of the major goals of aging research is to understand how cells gradually degenerate overtime. Decades of
work by molecular and cell biologicals have discovered several conserved hallmarks of cellular aging, including
mitochondrial dysfunction and vacuole/lysosome defects. These aging hallmarks are usually studied one at a
time and left the causes and connections between them largely unknown. What are the triggers and connections
between molecular events that step-by-step culminate at the different hallmarks of aging? Without the big picture
of how each protein changes in a proteome, often the best we can do is guess and try when it comes to the
causes and connections between these hallmarks. To fill the gaps, we have developed and implemented a new
high-throughput imaging method to systematically track the fate of each individual protein, including its expres-
sion, localization, aggregation, and timing of these changes (4D fate map), during the replicative aging of budding
yeast. The ongoing 4D fate mapping effort has demonstrated its value in revealing novel age-related molecular
signatures and the primary causes for the well-known hallmarks of aging. A representative example from our
pilot fate mapping effort is that the age-associated reduction of Tom70 is a key event of mitochondrial aging.
Overexpressing Tom70 can prevent the age-associated defects in mitochondrial biogenesis and vacuole acidi-
fication--two hallmarks of cellular aging. The goal of this proposal is to take a deep dive into the molecular mech-
anisms of these novel Tom70 functions, which will serve as an example of using proteome fate mapping to reveal
unknown causes and connections of aging hallmarks (Aim 1 and Aim 2). As our preliminary study has cleared
the technical barriers, we will finish the mapping of entire yeast proteome within this grant cycle. The completion
of fate mapping (Aim 3) will not only complement the other two aims by unfolding additional mechanisms that
contribute to the aging of mitochondria and vacuole (Aim 1 and Aim 2) but also fill the gaps between all other
aging hallmarks. This is exemplified by our preliminary results that the ongoing fate mapping provided an unex-
pected mechanism of Tom70 reduction during aging. We expect to reveal additional mechanisms of Tom70
reduction and mitochondrial/vacuolar aging when fate mapping covers more proteins. Together, this project will
advance both the depth and breadth of our understanding of aging and provide examples of how the fate map
(Aim 3) can be used to comprehensively understand the multifactorial causes of aging hallmarks (e.g., mitochon-
drial and vacuole defects in Aim 1 and Aim 2). Mining the 4D map of proteome aging by the research community
will systematically unveil previous unknown mechanisms and connections between different aging hallmarks.
The completion of this project will benefit researchers seeking the triggers and connections between different
aging hallmarks.

## Key facts

- **NIH application ID:** 10523016
- **Project number:** 1R01AG075201-01A1
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** Chuankai Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $607,996
- **Award type:** 1
- **Project period:** 2022-08-15 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10523016

## Citation

> US National Institutes of Health, RePORTER application 10523016, Multidimensional mapping of proteome changes and mechanisms underlying yeast replicative aging (1R01AG075201-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10523016. Licensed CC0.

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