AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD + elevation
Open accessAbstract
AMPK activation is beneficial for cellular homeostasis and senescence prevention. However, the molecular events involved in AMPK activation are not well defined. In this study, we addressed the mechanism underlying the protective effect of AMPK on oxidative stress-induced senescence. The results showed that AMPK was inactivated in senescent cells. However, pharmacological activation of AMPK by metformin and berberine significantly prevented the development of senescence and, accordingly, inhibition of AMPK by Compound C was accelerated. Importantly, AMPK activation prevented hydrogen peroxide-induced impairment of the autophagic flux in senescent cells, evidenced by the decreased p62 degradation, GFP-RFP-LC3 cancellation, and activity of lysosomal hydrolases. We also found that AMPK activation restored the NAD(+) levels in the senescent cells via a mechanism involving mostly the salvage pathway for NAD(+) synthesis. In addition, the mechanistic relationship of autophagic flux and NAD(+) synthesis and the involvement of mTOR and Sirt1 activities were assessed. In summary, our results suggest that AMPK prevents oxidative stress-induced senescence by improving autophagic flux and NAD(+) homeostasis. This study provides a new insight for exploring the mechanisms of aging, autophagy and NAD(+) homeostasis, and it is also valuable in the development of innovative strategies to combat aging.
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Autophagy impairment incurred through lysosomal dysfunction has been described in cellular senescence and shown to regulate SASP.
“Autophagy impairment incurred through lysosomal dysfunction has recently been described in cellular senescence and shown to regulate SASP [57], [72], [73], [74], [75].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [72]
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- Authors
- Han, X., Tai, H., Wang, X., Wang, Z., Zhou, J., Wei, X., Ding, Y., Gong, H., Mo, C., Zhang, J., Qin, J., Ma, Y., Huang, N., Xiang, R., & Xiao, H.
- Affiliations
- Sichuan University (CN)
- Nankai University (CN)
- Corresponding author
- Xiao, Hengyi
- ORCID
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2016-02-18
- Volume
- 15
- Issue
- 3
- Pages
- 416-427
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC4854918
- OpenAlex
- W2273828757
- Cited by
- 302
- References
- 39
- Citations by year
- 2026: 20 · 2025: 40 · 2024: 30 · 2023: 35 · 2022: 41 · 2021: 33 · 2020: 38 · 2019: 17 · 2018: 21 · 2017: 19 · 2016: 8
- FWCI
- 20.30
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Aging Cell (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81273224)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- 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
- AMPK activation, cellular senescence, oxidative stress, autophagic flux, NAD+ homeostasis, NAD+ salvage pathway, metformin, berberine, hydrogen peroxide, p62 degradation, lysosomal enzymes, mTOR, SIRT1, aging
- MeSH terms
- Animals, Autophagy, Cell Nucleus, Enzyme Activation, Humans, Hydrogen Peroxide, Lysosomes, NAD, Cellular Senescence, Oxidative Stress, Cytoprotection, Protein Transport, NIH 3T3 Cells, Intracellular Space, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases, Human Umbilical Vein Endothelial Cells
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