Increase of circulating IGFBP-4 following genotoxic stress and its implication for senescence
- Luigi Vanvitelli Campania University, Italy
- ASL Napoli 1, Italy
- National Research Council (CNR), Italy
Abstract
Senescent cells secrete several molecules, collectively named senescence-associated secretory phenotype (SASP). In the SASP of cells that became senescent following several in vitro chemical and physical stress, we identified the IGFBP-4 protein that can be considered a general stress mediator. This factor appeared to play a key role in senescence-paracrine signaling. We provided evidences showing that genotoxic injury, such as low dose irradiation, may promote an IGFBP-4 release in bloodstream both in mice irradiated with 100 mGy X-ray and in human subjects that received Computer Tomography. Increased level of circulating IGFBP-4 may be responsible of pro-aging effect. We found a significant increase of senescent cells in the lungs, heart, and kidneys of mice that were intraperitoneally injected with IGFBP-4 twice a week for two months. We then analyzed how genotoxic stressors may promote the release of IGFBP-4 and the molecular pathways associated with the induction of senescence by this protein.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
Regione Campania (CUP B23D18000250007)
- Umberto Galderisi
Regione Campania (CUP B23D18000250007)
- Gianfranco Peluso
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: The animals were handled in compliance with the protocols that were approved by the Animal Care and Use Committee of Luigi Vanvitelli Campania University. Italian Ministry of Health ethical approval n. 67/2012 A
Human subjects: Bone marrow aspirate samples were obtained from healthy donors (age 10-18 years) after informed consent. Campania Region Ethical Committee approval n. 317/2016 PR
Reviewing Editor
- Jean-Pierre Michel, University of Geneva, Switzerland
Version history
- Received: December 17, 2019
- Accepted: March 29, 2020
- Accepted Manuscript published: March 30, 2020 (version 1)
- Version of Record published: April 6, 2020 (version 2)
- Version of Record updated: July 1, 2022 (version 3)
Copyright
© 2020, Alessio et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Increase of circulating IGFBP-4 following genotoxic stress and its implication for senescence
eLife 9:e54523.
https://doi.org/10.7554/eLife.54523
Further reading
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- Medicine
- Stem Cells and Regenerative Medicine
Intermittent fasting (IF) has been shown to reduce cardiovascular risk factors in both animals and humans, and can protect the heart against ischemic injury in models of myocardial infarction. However, the underlying molecular mechanisms behind these effects remain unclear. To shed light on the molecular and cellular adaptations of the heart to IF, we conducted comprehensive system-wide analyses of the proteome, phosphoproteome, and transcriptome, followed by functional analysis. Using advanced mass spectrometry, we profiled the proteome and phosphoproteome of heart tissues obtained from mice that were maintained on daily 12- or 16 hr fasting, every-other-day fasting, or ad libitum control feeding regimens for 6 months. We also performed RNA sequencing to evaluate whether the observed molecular responses to IF occur at the transcriptional or post-transcriptional levels. Our analyses revealed that IF significantly affected pathways that regulate cyclic GMP signaling, lipid and amino acid metabolism, cell adhesion, cell death, and inflammation. Furthermore, we found that the impact of IF on different metabolic processes varied depending on the length of the fasting regimen. Short IF regimens showed a higher correlation of pathway alteration, while longer IF regimens had an inverse correlation of metabolic processes such as fatty acid oxidation and immune processes. Additionally, functional echocardiographic analyses demonstrated that IF enhances stress-induced cardiac performance. Our systematic multi-omics study provides a molecular framework for understanding how IF impacts the heart’s function and its vulnerability to injury and disease.
