Discovery of a small peptide that increases yeast lifespan by enhancing the function of APCCdh1 in nondividing quiescent cells
Abstract
Aging is characterized by molecular hallmarks conserved from yeast to humans. One such hallmark, senescence, is an irreversible nondividing state that promotes aging. We previously reported that mutants of the yeast anaphase-promoting complex (APC) shorten the lifespan of both dividing and nondividing cells. Here, we propose that activation of the APC will promote the maintenance of quiescent yeast cells, thereby delaying senescence and aging. We observed that APC activity in aging quiescent cells becomes increasingly impaired, as the APC substrates Clb1 and Mps1 accumulated within aging cells reintroduced back into the cell cycle. To identify peptide activators of the APC, we used a yeast 2-hybrid screen to recover peptides that interacted with the APC subunit Apc10. Recovered peptides were tested for their effects on the replicative lifespan (RLS) of dividing cells and the chronological lifespan (CLS) of nondividing cells. Several peptides increased the RLS of wild-type cells, but only one peptide (C43-4) increased CLS, which requires the APC Cdh1 coactivator but not the Cdc20 coactivator. In cells expressing C43-4, Clb1 and Mps1 levels remained low when aging quiescent cells were reintroduced back into the cell cycle. The addition of a synthetic C43-4 to aging quiescent cells increased CLS even when added at late stages of aging. Mutations to APC subunits and coactivators blocked the ability of C43-4 to extend CLS. Htz1, which shares sequence homology with C43-4, was found to suppress APC mutant phenotypes and stabilize Apc10. We individually mutated the 6 amino acids in C43-4 that were shared with Htz1; one of the mutants disrupted the C43-4-Apc10 2-hybrid interaction and abolished the C43-4-dependent increase in CLS. C43-4 action is evolutionarily conserved, as C43-4 increased Caenorhabditis elegans lifespan in a daf-16- and aak-2-dependent manner. Our results describe the discovery of an evolutionarily conserved translational peptide that is the first of its kind to specifically activate the anti-aging APCCdh1 complex.
Related
- Lifespan accumulated differences in semantic memory structure contribute to increases in episodic false memories
- Breakdown of Adiabatic Scaling and Noise-induced Functional Synchronization in Deeply Quiescent Excitable Systems
- An atlas of the C. elegans starvation response reveals that transcription is necessary to initiate transcriptional silencing in quiescent primordial germ cells
- Transcriptomic and proteomic analysis of quiescent epimastigotes as a resource for investigating Trypanosoma cruzi persistence
- LIAISON ® Calprotectin for the prediction of relapse in quiescent ulcerative colitis: The EuReCa study
BibTeX
@article{harris2026discovery,
title = {{Discovery of a small peptide that increases yeast lifespan by enhancing the function of APCCdh1 in nondividing quiescent cells}},
author = {Rachel E Harris and Spike D Postnikoff and Nishita K Shukla and Alexandra H Harkness and Hannah M Brooks and Abd-Al-Wahab Khawaja and Mackenzie E Malo and Carlos Zapien-Verdugo and Brandon M Waddell and Cheng-Wei Wu and Troy Anthony Alan Harkness},
journal = {Genetics},
year = {2026},
month = sep,
doi = {10.1093/genetics/iyag249},
url = {https://doi.org/10.1093/genetics/iyag249},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Discovery of a small peptide that increases yeast lifespan by enhancing the function of APCCdh1 in nondividing quiescent cells
AU - Rachel E Harris
AU - Spike D Postnikoff
AU - Nishita K Shukla
AU - Alexandra H Harkness
AU - Hannah M Brooks
AU - Abd-Al-Wahab Khawaja
AU - Mackenzie E Malo
AU - Carlos Zapien-Verdugo
AU - Brandon M Waddell
AU - Cheng-Wei Wu
AU - Troy Anthony Alan Harkness
PY - 2026
DA - 2026/09/16
JO - Genetics
DO - 10.1093/genetics/iyag249
UR - https://doi.org/10.1093/genetics/iyag249
AB - Aging is characterized by molecular hallmarks conserved from yeast to humans. One such hallmark, senescence, is an irreversible nondividing state that promotes aging. We previously reported that mutants of the yeast anaphase-promoting complex (APC) shorten the lifespan of both dividing and nondividing cells. Here, we propose that activation of the APC will promote the maintenance of quiescent yeast cells, thereby delaying senescence and aging. We observed that APC activity in aging quiescent cells becomes increasingly impaired, as the APC substrates Clb1 and Mps1 accumulated within aging cells reintroduced back into the cell cycle. To identify peptide activators of the APC, we used a yeast 2-hybrid screen to recover peptides that interacted with the APC subunit Apc10. Recovered peptides were tested for their effects on the replicative lifespan (RLS) of dividing cells and the chronological lifespan (CLS) of nondividing cells. Several peptides increased the RLS of wild-type cells, but only one peptide (C43-4) increased CLS, which requires the APC Cdh1 coactivator but not the Cdc20 coactivator. In cells expressing C43-4, Clb1 and Mps1 levels remained low when aging quiescent cells were reintroduced back into the cell cycle. The addition of a synthetic C43-4 to aging quiescent cells increased CLS even when added at late stages of aging. Mutations to APC subunits and coactivators blocked the ability of C43-4 to extend CLS. Htz1, which shares sequence homology with C43-4, was found to suppress APC mutant phenotypes and stabilize Apc10. We individually mutated the 6 amino acids in C43-4 that were shared with Htz1; one of the mutants disrupted the C43-4-Apc10 2-hybrid interaction and abolished the C43-4-dependent increase in CLS. C43-4 action is evolutionarily conserved, as C43-4 increased Caenorhabditis elegans lifespan in a daf-16- and aak-2-dependent manner. Our results describe the discovery of an evolutionarily conserved translational peptide that is the first of its kind to specifically activate the anti-aging APCCdh1 complex.
SN - 0016-6731
SN - 1943-2631
ER -