# Regulation of lifespan

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $324,925

## Abstract

Project Summary
The aging population and coincident rise in associated diseases demand a better understanding of the basic
mechanisms of aging to design appropriate interventions and prolong human health. Elucidating the molecular
mechanisms of the processes that slow aging, such as lifespan extension by caloric or dietary restriction,
would provide prime candidates for therapeutic intervention. Model organisms have allowed major advances
in defining aging mechanisms due to their exceptionally powerful genetics and analytical tools, and because
these processes are evolutionarily conserved from humans to yeasts. We discovered a new pathway in
Schizosaccharomyces pombe that both regulates autophagy and extends lifespan. Autophagy is a process
that degrades and recycles proteins and organelles, and has been linked to lifespan and diseases associated
with human aging. We found that both autophagy and lifespan are regulated through the cyclin-dependent
kinase Pef1, an ortholog of human Cdk5. Pef1 acts with its cyclin Clg1 to limit lifespan and autophagy, and is
opposed by the effector kinase Cek1 that extends lifespan and increases autophagy levels. The Clg1-Pef1-
Cek1 pathway acts independently of TOR, the only other pathway known to regulate both lifespan and
autophagy, but how these processes are controlled by the Pef1 pathway is unknown. Aim 1 will test the
hypothesis that the Pef1 pathway senses nutrients to control lifespan and autophagy. This aim will be
significant for testing the linkage between autophagy and lifespan extension by caloric or dietary restriction.
Establishing the mechanism by which the Pef1 pathway regulates lifespan and autophagy requires knowing
the downstream effectors, and Aim 2 describes a novel chemical genomics approach to identify Pef1 targets.
We modified the Pef1 kinase to allow selective binding of ATP analogs that tag kinase substrates to allow their
isolation, and used the Pef1 variant to identify the substrates. We identified substrates with predicted roles in
autophagy and lifespan, as well as substrates that we hypothesize mediate Pef1 control through signaling
pathways. Aim 2 will validate the substrates and identify substrates of the effector kinase Cek1. Aim 3 will
determine how the phosphorylation of Pef1 and Cek1 substrates affects specific processes in lifespan and
autophagy control, and will also use high-throughput functional characterization of substrates to reveal
signaling pathways regulated by the Pef1 pathway. The strong functional homology between Pef1 and human
Cdk5 indicates that the Clg1-Pef1-Cek1 pathway, its substrates and functions will be conserved in humans,
which we will also test in Aim 3. The results of these proposed studies will provide a mechanistic framework
for a new, conserved lifespan and autophagy-regulating pathway with important ramifications for healthy
human aging.

## Key facts

- **NIH application ID:** 9926773
- **Project number:** 5R01AG051601-05
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Kurt W Runge
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $324,925
- **Award type:** 5
- **Project period:** 2016-05-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926773

## Citation

> US National Institutes of Health, RePORTER application 9926773, Regulation of lifespan (5R01AG051601-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9926773. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*