Melatonin reverses H 2 O 2 ‐induced premature senescence in mesenchymal stem cells via the SIRT 1‐dependent pathway
Open accessAbstract
Mesenchymal stem cells ( MSC s) represent an attractive source for stem cell‐based regenerative therapy, but they are vulnerable to oxidative stress‐induced premature senescence in pathological conditions. We previously reported antioxidant and antiarthritic effects of melatonin on MSC s against proinflammatory cytokines. In this study, we hypothesized that melatonin could protect MSC s from premature senescence induced by hydrogen peroxide (H 2 O 2 ) via the silent information regulator type 1 ( SIRT 1)‐dependent pathway. In response to H 2 O 2 at a sublethal concentration of 200 μ m , human bone marrow‐derived MSC s ( BM ‐ MSC s) underwent growth arrest and cellular senescence. Treatment with melatonin before H 2 O 2 exposure cannot significantly prevent premature senescence; however, treatment with melatonin subsequent to H 2 O 2 exposure successfully reversed the senescent phenotypes of BM ‐ MSC s in a dose‐dependent manner. This result was made evident by improved cell proliferation, decreased senescence‐associated β ‐galactosidase activity, and the improved entry of proliferating cells into the S phase. In addition, treatment with 100 μ m melatonin restored the osteogenic differentiation potential of BM ‐ MSC s that was inhibited by H 2 O 2 ‐induced premature senescence. We also found that melatonin attenuated the H 2 O 2 ‐stimulated phosphorylation of p38 mitogen‐activated protein kinase, decreased expression of the senescence‐associated protein p16 INK 4 α , and increased SIRT 1. Further molecular experiments revealed that luzindole, a nonselective antagonist of melatonin receptors, blocked melatonin‐mediated antisenescence effects. Inhibition of SIRT 1 by sirtinol counteracted the protective effects of melatonin, suggesting that melatonin reversed the senescence in cells through the SIRT 1‐dependent pathway. Together, these findings lay new ground for understanding oxidative stress‐induced premature senescence and open perspectives for therapeutic applications of melatonin in stem cell‐based regenerative medicine.
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Melatonin decreases p53, p21, and p16 proteins and enhances SIRT1 activity in H2O2-induced senescence.
“Melatonin-induced decrease in p53, p21 and p16 proteins, together with enhanced SIRT1 activity, have also been reported in the context of H2O2-induced senescence [458,459].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [459]
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- Authors
- Zhou, L., Chen, X., Liu, T., Gong, Y., Chen, S., Pan, G., Cui, W., Luo, Z., Pei, M., Yang, H., & He, F.
- Affiliations
- Soochow University (CN)
- First Affiliated Hospital of Soochow University (CN)
- Sun Yat-sen University (CN)
- Nanfang Hospital (CN)
- West Virginia University (US)
- Corresponding author
- He, Fan
- ORCID
- Venue
- Journal of Pineal Research
- Publisher
- Wiley
- Published
- 2015-07-07
- Volume
- 59
- Issue
- 2
- Pages
- 190-205
- ISSN
- 0742-3098 (ISSN-L)
- 1600-079X
- PMC
- PMC4523475
- OpenAlex
- W1943985293
- Cited by
- 158
- References
- 57
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 11 · 2023: 10 · 2022: 20 · 2021: 17 · 2020: 14 · 2019: 13 · 2018: 19 · 2017: 17 · 2016: 11 · 2015: 5
- FWCI
- 9.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of Pineal Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Natural Science Foundation of China (51203194, 51103182, 21204056, 31270995, 81320108018)
- National Institutes of Health (R03 AR062763-01A1)
- Natural Science Foundation of Jiangsu Province (BK20140323, BK2012173)
- Jiangsu Provincial Special Program of Medical Science (BL2012004)
- Jiangsu Provincial Clinical Orthopedic Center
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry
- Science and Technology Program of Guangzhou
- Topics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- melatonin, mesenchymal stem cells, premature senescence, hydrogen peroxide, oxidative stress, SIRT1, p38 MAPK, osteogenic differentiation, bone marrow-derived mesenchymal stem cells, senescence reversal, luzindole, sirtinol, regenerative medicine
- MeSH terms
- Benzamides, Humans, Hydrogen Peroxide, Melatonin, Naphthols, S Phase, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, MAP Kinase Signaling System, p38 Mitogen-Activated Protein Kinases, Sirtuin 1, Mesenchymal Stem Cells
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