Hallmarks and Biomarkers of Skin Senescence: An Updated Review of Skin Senotherapeutics
Abstract
:1. Introduction
2. Search Strategy
3. Cellular Senescence
4. Other Nonsenescent Forms of Cell Cycle Arrest
5. Hallmarks of Senescence
5.1. Stable Cell Cycle Arrest
5.2. Metabolic Changes
5.3. Morphological Changes
5.4. Epigenetic Alterations
5.5. DNA Damage and Persistent DNA Damage Response
5.6. Apoptosis Resistance
5.7. Secretory Phenotype
5.8. Reactive Oxygen Species
5.9. Biomarkers of Cellular Senescence
6. Hallmarks and Biomarkers of Skin Aging
7. Skin Senotherapy and Antioxidant Compounds
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Senescence | Quiescence | Terminal Differentiation | T-Cell Exhaustion | References | |
---|---|---|---|---|---|
Type of cell cycle arrest | Generally irreversible | Reversible | Generally irreversible | Largely irreversible | [26,27,29,30] |
Cause | Repetitive stimulation; DNA damage agents; stress signals | Signals of mitogen deprivation; contact inhibition | Genetically preprogramed | Continuous antigenic stimulation | [26,27,31,32] |
Typical features | Large flat cells | Reduced cell size | n/a | n/a | [33,34] |
Cell cycle arrest driver: ↑ p16, p21, p53 | CDK inhibitors: ↑ p21,27, 57 | p21, p27, and p57 | ↑ p27, p15; ↓ cyclin E-Cdk2, Cdc25A | [26,27,31,35] | |
↑ Macromolecular damage ↓ Telomere length, telomerase activity | Does not exhibit macromolecular damage | Does not exhibit macromolecular damage | ↓ Telomere length, telomerase activity | [36,37,38] | |
↑ SA-β-gal activity | Does not result in the upregulation of SA-β-gal activity | Does not result in the upregulation of SA-β-gal activity | Does not result in the upregulation of SA-β-gal activity | [39,40] | |
n/a | n/a | n/a | ↑ Inhibitory receptors: PD1, TIM3, LAG3, CTLA4, TIGIT | [41] | |
↑ Glycolysis | ↓↑ Glycolysis (depending on cell type) | n/a | ↓ Glycolysis | [42,43,44] | |
Cytokine pattern | SASP, proinflammatory cytokines: ↑ IL-1, IL-6, IL-8, IFN-γ, TNF | n/a | n/a | ↓ IL-2 ↓ TNF ↓ IFN-γ, β-chemokines | [45,46] |
Epigenetic changes | ↑ SAHF Abnormal DNA methylation | ↑ H3K27me3 chromatin modifications; expression level of several histones is strongly reduced | ↑ H3K9me3 and H3K27me3; reduced levels of global DNA methylation; enhancers are enriched for H3K27me3 and DNA methylation, which is associated with the lower expression of their target genes | Exhaustion-associated DNA methylation patterns | [37,47,48,49] |
Hallmarks of Senescence | Biomarker | Observation | Detection Method | References |
---|---|---|---|---|
Cell cycle arrest | p16/pRB axis | ↑ p16 ↑ pRb ↓ Phospho-pRb | WB, IHC, IF | [56,115,116,117,118,119] |
p53/p21 axis | ↑ p21 ↑ p53 ↑ Phospho-p53 | |||
Absence of proliferation | ↓ Ki67 ↓ PCNA | IHC, IF | [24,120,121] | |
Decrease in/absence of DNA synthesis | ↓ BrdU, EdU | Staining incorporation, immunofluorescence | [122] | |
Metabolic adaptations | SA-β-gal | ↑ | NIR Fluorescence Enzymatic staining | [123,124,125] |
α-fucosidase | ↑ | Fluorescence Enzymatic staining | [64,126] | |
Lipofuscin | ↑ | Dye incorporation (SSB, GL13) Fluorescence | [127,128] | |
Morphological changes | Wide and flattened cells High vacuolization | n/a | IF Scanning electron microscopy Light microscopy Flow cytometry | [129,130] |
Lamin B1 | ↓ | qPCR, IF, WB | [131] | |
Plasma membrane proteins | ↑ ICAM-1, DEP1 | Immunohistochemistry IF, WB, flow cytometry | [132] | |
Epigenetic alterations | SAHF | ↑ PML bodies ↑ H3K9 methylation | IF | [133] |
DNA damage | γH2AX 53BPI ATM ATR TIF | ↑ | IF | [89] |
Telomere shortening | ↓ | qPCR, FISH | [134,135] | |
Apoptosis resistance | Annexin V Cleaved caspases Cleaved PARP | ↓/absent | IF IHC WB | [136,137,138,139,140] |
Blunt ends of double-stranded DNA breaks | - | TUNEL assay | [141] | |
Secretory phenotype | SASPs | ↑ IL-1, IL-6, IL-8, ↑ TNF-α, GROα/β, ↑ MMP-1, MMP-3, MMP-9 ↑ IGFBPs ↑ SERPINs ↑ TIMPs | ELISA Immunofluorescence WB SASP-responsive alkaline phosphatase assay | [142,143,144,145] |
ROS | O2, H2O2, O2•−, HO• | ↑ | Chemiluminescent oxygen detection, fluorometry, flow cytometry | [146,147] |
Polyphenol | Route of Administration | Aging Inductor | Research Model | Mechanism | Main Senotherapeutic Effects | Reference |
---|---|---|---|---|---|---|
Apigenin | In vitro | UVA and UVB | Human dermal fibroblasts | ↓ ROS ↓ NF-kB pathway ↓ MAPK ↓ MMP-1 | ↑ Viability ↑ Collagen synthesis ↑ DNA repair | [148,168] |
Topical | UVA | Mice | ↓ ROS ↓ NF-kB pathway ↓ MAPK ↓ MMP-1 | ↑ Dermal thickness ↑ Collagen deposition | [169] | |
Baicalin | In vitro | UVB | Human dermal fibroblasts, human skin samples | ↓ ROS ↓ MMP-1, MMP-3 ↓ p16, p21, p53 | ↑ Collagen synthesis ↑ Viability ↓ DNA damage ↓ Apoptosis | [81] |
In vitro | UVC | Human keratinocytes | ↓ ROS | ↓ DNA damage | [170] | |
Ferulic acid | In vitro | UVA | Human dermal fibroblasts | ↓ ROS ↑ SOD1 ↑ CAT ↓ p16 ↓ MMP-1, -3 | ↑ Proliferation and cell cycle ↑ ECM reconstruction | [171] |
Fisetin | In vitro | Hydrogen peroxide | Human keratinocytes | ↓ ROS ↓ NF-kB ↓ iNOS ↓ COX-2 ↓ IL-1β, -6, TNF-α | ↓ SASP secretion ↑ Viability | [172] |
In vitro | UVB | Human dermal fibroblasts | ↓ ROS ↓ MAPK/AP-1/MMP | ↓ SASP secretion ↓ Collagen degradation | [173] | |
Gallic acid | In vitro | UVB | Human dermal fibroblasts | ↓ ROS ↓ MMP-1 ↓ IL-6 | ↑ Procollagen type I | [174] |
Topical and oral | UVB | Mice | ↑ TGF-β1 ↓ MMP-1 ↓ IL-6 | ↓ Wrinkle formation ↓ Skin dryness ↑ Procollagen type I ↑ Elastin | ||
Genistein | Topical | UVB | Mice | ↓ ROS ↓ DNA pyrimidine dimer formation | ↓ DNA damage | [175] |
Luteolin | In vitro and topical | UVA | Human dermal fibroblasts, human keratinocytes, and human skin explants | ↓ ROS ↓ MMP-1 ↓ IL-6, -20 ↓ p38/MAPK | ↓ SASP secretion ↓ Collagen degradation ↓ Hyaluronic acid degradation | [176] |
Naringenin | Intraperitoneal | UVB | Mice | ↓ ROS ↓ MMP-9 ↓ TNF-α, IFN-γ ↓ IL-1β, -4, -5, -6, -12, -13, -17, -22, -23 | ↓ SASP secretion ↓ Inflammatory infiltrations | [177] |
Topical | UVB | Mice | ↓ ROS ↓ IL-1β, -6, -10, TNF-α | ↓ SASP secretion | [178] | |
Nectandrin B | In vitro | Cell passage ≥72 | Human diploid fibroblasts | ↓ ROS ↑ AMPK ↓ p16, p21, p27, p53 ↓ Cyclin D1 ↓ SA-β-gal ↓ Caveolin-1 | ↓ Senescence ↓ Apoptosis | [179] |
Piceatannol | In vitro | UVB | Human keratinocytes | ↓ ROS ↑ GSH ↓ NF-kB ↓ MMP-1 | ↓ Melanogenesis ↑ Collagen synthesis ↓ Photoaging | [180] |
Quercetin | In vitro | Cell passage ≥17 | Human dermal fibroblasts | ↓ ROS ↑ SOD2, -3 ↑ CAT ↓ p16, p53 | ↓ Senescence ↑ Mitochondrial membrane potential | [181] |
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Bulbiankova, D.; Díaz-Puertas, R.; Álvarez-Martínez, F.J.; Herranz-López, M.; Barrajón-Catalán, E.; Micol, V. Hallmarks and Biomarkers of Skin Senescence: An Updated Review of Skin Senotherapeutics. Antioxidants 2023, 12, 444. https://doi.org/10.3390/antiox12020444
Bulbiankova D, Díaz-Puertas R, Álvarez-Martínez FJ, Herranz-López M, Barrajón-Catalán E, Micol V. Hallmarks and Biomarkers of Skin Senescence: An Updated Review of Skin Senotherapeutics. Antioxidants. 2023; 12(2):444. https://doi.org/10.3390/antiox12020444
Chicago/Turabian StyleBulbiankova, Darya, Rocío Díaz-Puertas, Francisco Javier Álvarez-Martínez, María Herranz-López, Enrique Barrajón-Catalán, and Vicente Micol. 2023. "Hallmarks and Biomarkers of Skin Senescence: An Updated Review of Skin Senotherapeutics" Antioxidants 12, no. 2: 444. https://doi.org/10.3390/antiox12020444