Aging activates latent enhancers that can be reversed withexercise
- 1Victor Chang Cardiac Research Institute, Sydney, NSW, Australia
Abstract
Aging profoundly alters the genome's regulatory landscape, but the properties of age-acquired enhancers, including how they are selected and sustained in aged animals are unclear. We used single-cell multiomics in the mouse heart to identify age-responsive cis-regulatory elements and endurance exercise to understand which of these elements can be attenuated. Aging increased AP-1 engagement at more than 100,000 regulatory loci across cardiac cell types. Exercise opposed most of these gains. Despite low endogenous accessibility, age-gained enhancer sequences drove reporter activity comparable to stable elements, revealing substantial latent transcriptional potential. Local sequence features distinguished responsiveness to aging and exercise. Reporter perturbations implicated sequence outside the AP-1 core, and mutagenesis localized informative positions to dispersed segments of dynamic enhancers. These enhancers were IL-1-sensitive and were preferentially responsive to neutralization of the cytokine in vivo. AP-1 inhibition further opposed age-associated transcription. Together, these findings support a model in which aging engages latent cell-type specific enhancers that are sustained in an active state by ongoing trans signaling. Aging therefore changes the deployment of existing regulatory information, while the acquired activity remains responsive to changes in signaling even in old age.
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BibTeX
@misc{clarke2026aging,
title = {{Aging activates latent enhancers that can be reversed withexercise}},
author = {J. Clarke and F. Wu and V. Janbandhu and S. Bagot and D. Zheng and P. M. Puccetti and D. Cheng and X. Zhuang and H. E. Maksura and X. Zhang and A. G. Rajal and J. Feng and Y. Tran and A. R. Pinto and P. K. Koo and C. D. Cox and R. P. Harvey and L. W. Jones and T. Tammela and E. S. Wong},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.02.763799},
url = {https://www.biorxiv.org/content/10.64898/2026.11.02.763799v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Aging activates latent enhancers that can be reversed withexercise
AU - J. Clarke
AU - F. Wu
AU - V. Janbandhu
AU - S. Bagot
AU - D. Zheng
AU - P. M. Puccetti
AU - D. Cheng
AU - X. Zhuang
AU - H. E. Maksura
AU - X. Zhang
AU - A. G. Rajal
AU - J. Feng
AU - Y. Tran
AU - A. R. Pinto
AU - P. K. Koo
AU - C. D. Cox
AU - R. P. Harvey
AU - L. W. Jones
AU - T. Tammela
AU - E. S. Wong
PY - 2026
DA - 2026/11/02
PB - bioRxiv
DO - 10.64898/2026.11.02.763799
UR - https://www.biorxiv.org/content/10.64898/2026.11.02.763799v1
AB - Aging profoundly alters the genome's regulatory landscape, but the properties of age-acquired enhancers, including how they are selected and sustained in aged animals are unclear. We used single-cell multiomics in the mouse heart to identify age-responsive cis-regulatory elements and endurance exercise to understand which of these elements can be attenuated. Aging increased AP-1 engagement at more than 100,000 regulatory loci across cardiac cell types. Exercise opposed most of these gains. Despite low endogenous accessibility, age-gained enhancer sequences drove reporter activity comparable to stable elements, revealing substantial latent transcriptional potential. Local sequence features distinguished responsiveness to aging and exercise. Reporter perturbations implicated sequence outside the AP-1 core, and mutagenesis localized informative positions to dispersed segments of dynamic enhancers. These enhancers were IL-1-sensitive and were preferentially responsive to neutralization of the cytokine in vivo. AP-1 inhibition further opposed age-associated transcription. Together, these findings support a model in which aging engages latent cell-type specific enhancers that are sustained in an active state by ongoing trans signaling. Aging therefore changes the deployment of existing regulatory information, while the acquired activity remains responsive to changes in signaling even in old age.
ER -