# Discovering the molecular mechanisms that determine replicative lifespan

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $539,604

## Abstract

SUMMARY
Cells divide a fixed number of times, termed replicative lifespan, before they stop dividing and senesce.
Acceleration of the alterations to biological macromolecules that characterize the normal replicative aging
process predisposes us to shortened replicative lifespan and conditions such as progeria. Despite the
fundamental importance of the replicative aging process, there are still huge gaps in our understanding of the
biological changes that cause aging and the molecular basis of these changes. Given that the mechanisms of
aging are highly conserved across eukaryotes, we use the unparalleled genetic power of budding yeast to gain
insight into the molecular mechanisms of replicative aging in all eukaryotes. Using the Mother Enrichment
Program (MEP) to isolate unprecedented quantities of old cells, we performed a systematic characterization of
the replicative aging process in yeast, with the intention of transferring our discoveries to mammalian systems.
Using the MEP, my laboratory has been performing a systems biology analysis of the aging process, really for
the first time in any organism. Our genome-wide mapping of nucleosome positions uncovered a global loss of
nucleosomes during aging, leading to transcriptional upregulation of every gene in the genome. By deep
sequencing of the genome during aging we discovered a global increase in retrotransposition, chromosomal
translocation, DNA amplification, rDNA instability, transfer of mitochondrial DNA into the nuclear genome and
DNA breaks during aging 1. We have now performed metabolomics analysis and ribosome profiling (Ribo-seq)
during aging, leading us to our current hypothesis and goal of discovering the molecular details of how protein
synthesis changes with aging, the beneficial consequences, and to leverage this information to extend lifespan
and healthspan.

## Key facts

- **NIH application ID:** 9932296
- **Project number:** 5R01AG050660-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Jessica K Tyler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $539,604
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932296

## Citation

> US National Institutes of Health, RePORTER application 9932296, Discovering the molecular mechanisms that determine replicative lifespan (5R01AG050660-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9932296. Licensed CC0.

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