Combined activation of the energy and cellular-defense pathways may explain the potent anti-senescence activity of methylene blue
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Methylene blue (MB) delays cellular senescence, induces complex-IV, and activates Keap1/Nrf2; however, the molecular link of these effects to MB is unclear. Since MB is redox-active, we investigated its effect on the NAD/NADH ratio in IMR90 cells. The transient increase in NAD/NADH observed in MB-treated cells triggered an investigation of the energy regulator AMPK. MB induced AMPK phosphorylation in a transient pattern, which was followed by the induction of PGC1α and SURF1: both are inducers of mitochondrial and complex-IV biogenesis. Subsequently MB-treated cells exhibited >100% increase in complex-IV activity and a 28% decline in cellular oxidants. The telomeres erosion rate was also significantly lower in MB-treated cells. A previous research suggested that the pattern of AMPK activation (i.e., chronic or transient) determines the AMPK effect on cell senescence. We identified that the anti-senescence activity of MB (transient activator) was 8-times higher than that of AICAR (chronic activator). Since MB lacked an effect on cell cycle, an MB-dependent change to cell cycle is unlikely to contribute to the anti-senescence activity. The current findings in conjunction with the activation of Keap1/Nrf2 suggest a synchronized activation of the energy and cellular defense pathways as a possible key factor in MB's potent anti-senescence activity.
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Multiple mechanisms are thought to underlie methylene blue antioxidant function, including Keap/Nrf2 pathway upregulation, MB to MBH2 cycling in mitochondria, complex IV induction and increased production of collagen 2A1 and elastin.
“Although not yet fully understood, multiple mechanisms are thought to underlie its antioxidant function, including Keap/Nrf2 pathway upregulation, MB to MBH2 (the reduced form of MB) cycling in mitochondria, complex IV induction and increased production of collagen 2A1 and elastin, two components of the extracellular matrix fundamental for skin preservation [79,80,104].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [104]
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- Authors
- Atamna, H., Atamna, W., Al-Eyd, G., Shanower, G., & Dhahbi, J. M.
- Affiliations
- California University of Science and Medicine (US)
- Geisinger College of Health Sciences (US)
- University of California, Riverside (US)
- Corresponding author
- Atamna, Hani
- ORCID
- Dhahbi, Joseph M.
- Venue
- Redox Biology
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 6
- Pages
- 426-435
- ISSN
- 2213-2317 (ISSN-L)
- PMC
- PMC4588422
- OpenAlex
- W1756479101
- Cited by
- 40
- References
- 63
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 3 · 2018: 9 · 2017: 3 · 2016: 3
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Redox Biology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institute of Aging of NIH (R15AG041414)
- American Federation for Aging Research (AFAR) Research Grant Program
- Ames Foundation to HA.
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- methylene blue, cellular senescence, NAD+/NADH ratio, AMPK, PGC-1α, SURF1, cytochrome c oxidase, mitochondrial biogenesis, redox-active molecules, telomere shortening, IMR-90 cells, AICAR
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Adenylate Kinase, Aminoimidazole Carboxamide, Cell Cycle, Cell Line, Electron Transport Complex IV, Drug Evaluation, Preclinical, Energy Metabolism, Humans, Methylene Blue, Mitochondria, NAD, Oxidation-Reduction, Phosphorylation, Protein Processing, Post-Translational, Ribonucleotides, Transcription Factors, Transcriptional Activation, Cellular Senescence, Mitochondrial Membranes, Telomere Homeostasis
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