Skin Aging, Cellular Senescence and Natural Polyphenols
Abstract
:1. Introduction
2. Cellular Senescence in Skin Aging
2.1. Biomarkers of Cellular Senescence in the Skin
2.1.1. Senescence-Associated Ultrastructural Changes
- Hypertrophy and increased granularity. In senescent cells, both an increase in size and, if adherent cells, a flattening of the shape can be observed [3]. For these changes, the activation of the mammalian target of the rapamycin (mTOR) signaling pathway is responsible [53]. These morphological changes are easily detectable by light microscopy and quantified by flow cytometry (as an increase in forward scatter, FSC parameters). However, though in situ and in vivo quantification can be a problem, changes in plasma membrane protein expression represent a promising new biomarker of senescence [54]. The size increase by up to nine times was found in senescent fibroblasts [3]. The size increasing with other senescence markers was also confirmed in aged keratinocytes [55] and in a model of UVB-induced senescence in human melanocytes [56]. The senescent nuclei of skin cells also showed hypertrophy. In particular, the mean nuclear area of fibroblasts was shown to be 255 μm2 at early passage, compared to 293 μm2 at later passage [57]. The increase in granular content in senescent cells can be monitored by transmission electron microscopy as intracellular electron-dense particles [58]. However, cell granularity levels can also be conveniently detected by flow cytometry as an increase in the side scatter (SSC) parameter. The increase in granularity in senescent human fibroblasts is a result of the intracellular deposit formation, including lipofuscin in lysosomes and glycogen particles [59,60]. In a model of the UVB-promoted senescence of melanocytes, the cell population showing a high granularity was mostly growth-arrested at G2/M phase [61];
- Increase in lysosomal mass and SA-β-Gal staining. The increase in the lysosomal mass in senescent cells is associated with the accumulation of old lysosomes and increased lysosomal biogenesis. Accumulated lipofuscin may be in line with the impaired lysosomal turnover mechanism [62]. Lysosomal biogenesis is largely controlled by the transcription factor EB (TFEB), an effector protein within the mTOR signaling pathway that regulates multiple lysosomal proteins. During senescence, it tends to be up- or down-regulated, making it difficult to use as a marker of senescence [63,64]. Alternatively, the detection of lipofuscin content can be used as a biomarker of lysosome accumulation, either by its typical autofluorescence properties and fluorescence-based methods, or by selective staining with Sudan black B, allowing for detection in cells, tissues and body fluids [65]. The term lipofuscin originates from the Greek words “lipo” (fat) and “fuscus” (dark) [1]. In addition, it is referred to as “aging fluorophore” or “aging pigment”. It is an insoluble material that mainly consists of a highly oxidized and crosslinked substrate, which are proteins, lipids and sugars. Transition metals also bind to lipofuscin and increase its intracellular cytotoxicity through the catalysis of ROS formation by the Fenton reaction. Lipofuscin is also present in small amounts in the cytosol (about 1% of the total intracellular content), while its cytotoxicity is suppressed by the macroautophagy activity of the cell. It preferentially accumulates in postmitotic tissue cells, such as neurons or muscle cells, which do not divide and are therefore unable to dilute the products of their damage (in the sense of the so called “garbage catastrophe theory of aging”) [66]. However, lipofuscin has also been shown to accumulate during the replicative senescence of human fibroblasts [67]. Lipofuscin accumulation has been detected in the basal layers of the aged epidermis [68]. The phototoxicity of visible light has been linked to accumulated lipofuscin in skin cells due to oxidative damage in nucleic acids, lipids and proteins, generating premutagenic DNA lesions and releasing pro-inflammatory cytokines and metalloproteinases, consequently exaggerating cell damage and skin aging [69]. The increase in the size and shape of lysosomes is mostly associated with an increase in the activity of the lysosomal enzyme, senescence-associated b-galactosidase (SA-β-Gal). Since SA-β-Gal is upregulated in senescent cells, its residual activity can be monitored at suboptimal pH 6.0. It is the most widely used marker of senescence in culture and tissue samples [70]. However, factors such as confluence during cell culture may contribute to the detection of a false positive signal [71]. Furthermore, this assay requires active enzymatic SA-β-Gal activity, which is often lost in fixed or cryopreserved tissues [72,73]. In addition, non-specific SA-β-Gal activity was detected in the early passage of adult melanocytes proliferating in culture [21]. The available methodologies allow, depending on the properties of a specific synthetic b-galactosidase substrate, for the quantification of senescent cells in in vitro models or tissues of an aged organism using a combination of flow cytometry or spectrofluorimetry with high-content image analysis [74]. SA-β-Gal activity has been successfully confirmed in human fibroblasts and keratinocytes undergoing replicative senescence in vitro, in skin samples or in the cells isolated from aged individuals [75,76,77,78,79]. Furthermore, SA-β-Gal has been used to confirm premature senescence in cultured fibroblasts, keratinocytes and melanocytes cells in response to various stressors, including UV light [43,50,80,81,82,83], cigarette smoke [84,85], ionization radiation [86], oxidants [87,88,89] or anticancer drugs [90];
- Accumulation of mitochondria. Senescent cells usually have a higher number of mitochondria and also display organelle enlargement [91]. Highly elongated or enlarged giant mitochondria were observed in senescent human foreskin diploid fibroblasts, with their population doubling between 90 and 94 times [91]. However, the mitochondrial membrane potential is reduced, which is associated with an increased ROS production and the release of mitochondrial enzymes, such as endonuclease G [92,93]. This is mainly due to the reduced specific autophagy of mitochondria, mitophagy, causing old and dysfunctional mitochondria to accumulate [94]. Reduced mitochondrial scission and excessive fusion, which likely occur to compensate for the dysfunction of mitochondria in senescent cells and to protect them from apoptosis and mitophagy [95], contribute to mitochondria enlargement [96]. Dysfunctional mitochondria also represent a major source of elevated ROS production in senescent cells, another important hallmark of senescence [97]. There is also a strong link between ROS-related mitochondrial damage and photoaging. The repetitive UVA exposure was found to be accompanied by a rise in mitochondrial DNA mutations. In particular, the photoaged skin comprises up to 10-fold more frequent mitochondrial DNA mutations compared to sun-protected skin [98,99,100]. Moreover, mitochondrial DNA mutations are positively associated with matrix metalloproteinase-1 (MMP-1) levels without the related increase in MMP-1 specific tissue inhibitors [101];
- Nuclear changes. Senescent nuclei may contain so termed senescence-associated heterochromatin foci (SAHFs), the silent domains that co-localize with H3K9me3 and heterochromatin protein 1 (HP1) and may lock cells in a senescent state by transcriptionally repressing genes involved in cell proliferation [102]. The SAHFs can be visualized by staining with 4′, 6-diamidino-2-phenylindole (DAPI) and appear as fluorescent spots representing condensed chromatin domains that block certain genes required for proliferation [12]. The long-term monitoring of senescent cells in vitro revealed the progressive proteolysis of histones 3 and 4 without DNA loss. A reduced histone content was also observed in nevus melanocytes, as compared to neighboring non-senescent melanocytes and keratinocytes in vivo [103]. These studies confirm the dramatic structural changes in chromatin in senescent cells.SAHFs are also implicated in the downregulation of lamin B1, a structural protein of the nuclear lamina/membrane [22,104]. Lamin B1 has been shown to be downregulated in cells undergoing mainly replicative senescence and OIS and UV-induced senescence in vitro [26,103,105,106], and also decline during the chronological aging of human skin in vivo [105], in senescent melanocytes within human nevi [103] and in the UV-exposed mouse skin epidermis [51]. The destabilization of nuclear integrity leads to other changes, such as a loss of constitutive heterochromatin condensation and the formation of cytoplasmic chromatin fragments that contain epigenetic tags associated with DNA damage [103]. SAHFs production is thought to be a compensatory mechanism that maintains constitutive heterochromatin [107]. SAHFs, however, are not a universal marker of senescence, but are observed especially in the case of OIS [17]. Lamin B1 downregulation preferentially depends on p53 and p16, but is independent of other signaling pathways associated with senescence, such as p38 mitogen-activated protein kinases (MAPK), NF-κB and DNA damage response (DDR) [108].
2.1.2. Changes in Cyclin-Dependent Kinase Inhibitors (CDKIs) Expression
2.1.3. Changes in Apoptosis Resistance
2.1.4. Senescence-Associated Secretory Phenotype
2.1.5. Metabolism Changes
2.1.6. Proteostasis Changes
2.1.7. Endoplasmic Reticulum (ER) Stress
2.1.8. Persistent DNA Damage
2.1.9. Pigmentation Changes and Skin Cellular Aging
3. Natural Polyphenols against Skin Cellular Aging
4. Polyphenols as Anti-Aging Cosmeceuticals
5. Cellular Aging of Skin and COVID-19 Pandemic
6. Summary and Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Polyphenol | Type of Skin Cells | Assay Conditions | Effect | Reference |
---|---|---|---|---|
Hydroxytyrosol and Oleuropein | neonatal human dermal fibroblasts | 1 μM hydroxytyrosol or 10 μM oleuropein | reduced SA-β-Gal-positive cell number and p16INK4A protein expression | [299] |
Apigenin | human foreskin fibroblasts | 10 or 20 μM for 24 h co-treated with bleomycin | decreased expression of IL-6, IL-8 and IL-1β mRNA; inhibited NF-κB activity | [300] |
NHDF | 15 mM 1 h before and after UVB-exposure | downregulated NER expression; inhibited nuclear fragmentation and Bax and caspase-3 expression | [175] | |
Kaempferol | human foreskin fibroblasts | 10 or 20 μM for 24 h co-treated with bleomycin | decreased expression of IL-6, IL-8 and IL-1β mRNA | [300] |
Quercetin | human foreskin fibroblasts | 10 or 20 μM for 24 h co-treated with bleomycin | decreased expression of IL-6, IL-8 and IL-1β mRNA; reduced SA-β-Gal | [300] |
Naringenin | human foreskin fibroblasts | 10 or 20 μM for 24 h co-treated with bleomycin | reduced SA-β-Gal | [300] |
Bergamot polyphenol fraction | HaCaT | UVB-exposed | modulation of IL-1β; restored telomere length and telomerase activity | [302] |
Genistein | NHDF and keratinocytes co-culture | 10 mM for 72 h after UVB exposure | inhibited IL-6 production; inhibited phosphorylation of p38, ERK and JNK | [303] |
Rooibos methanolic and aqueous extracts | HaCaT | sub-lethal concentrations (0.05–0.55 mg/mL) for 24 h after UVB exposure | inhibited viability and proliferation facilitating the removal of accumulating icIL-1a | [304] |
Honeybush aqueous extracts | HaCaT | 0.10–0.79 mg/mL for 24 h after UVB exposure | inhibited icIL-1a accumulation; increased caspase-3 activity in damaged cells (with opposing effect found for methanolic extract) | [304] |
Pomegranate fruit extract | NHEK | 10–40 mg/mL for 24 h before UVB exposure | inhibited phosphorylation of ERK1 and 2, JNK1 and 2 and p38; inhibited phosphorylation of IκBα and IKKα; inhibited translocation of NF-κB/p65 | [307] |
SKU-1064 skin fibroblasts | 5–60 mg/L for 2 h after UVB exposure | reduced activation of NF-κB; downregulation of caspase-3; increased G0/G1 phase arrest associated with DNA repair | [310] | |
Phloretin | HaCaT | 50–200 mg/mL 12 h after UVB exposure | decreased DNA damage; reduced phosphorylation of p53 and γ-H2AX; inhibited IL-6 and prostaglandin E2 | [308] |
Salidroside | NHDF | 1–10 mM for 24 h before UVB exposure | recovered viability; decreased SA-β-Gal-positive cells; relieved G1/G0 cell cycle arrest; suppressed p21CIP/Waf1 and p16INK4A expression; reduced MMP-1 activity; reduced IL-6 and TNF-α production | [305] |
Grape seed proanthocyanidins | NHEK | 10–50 mM for 3–6 h before UVB exposure | inhibited intracellular release of H2O2; inhibited photo-oxidative damage of lipids and proteins; inhibited oxidative DNA damage; inhibited phosphorylation of ERK1 and 2, JNK and p38 | [309] |
Glycyrrhizic acid | Hs68 foreskin fibroblasts | 10–25 mM for 16 h before UVB exposure | reduced ROS levels; restored Ca2+ levels; inhibited ER stress; reduced phosphorylation of p38 and JNK | [313] |
Gallic acid | NDHF, HaCaT | 0.1–10 mM for 24 h after UVB exposure | decreased IL-6; decreased MMP-1 levels; decreased ROS production; suppressed phosphorylation of AP-1 | [314] |
Piceatannol | NHEK | 0–2 mg/mL for 24 h before UVB exposure | suppressed ROS generation; reduced MMP-1 induction | [315] |
Fisetin | HaCaT | 1–20 mM for 12 h cotreated with H2O2 (500 mM) or pre-treatment for 6 h before TNF-α stimulation | reduced ROS production; inhibited IL-1β and IL-6 production; decreased iNOS and COX-2 expression; increased Nrf2-mediated HO-1 expression | [316] |
Brown pine leaf extract (BPLE) andtrans-communic acid (TCA) | HaCaT, reconstructed human skin models | BPLE (5, 10 μg/mL) and TCA (5, 10 μM) for 1 h before UVB exposure | inhibited MMP-1 expression; suppressed AP-1 expression; inhibited Akt and PI3K phosphorylation | [317] |
Orange peel extract | HaCaT | 0.1–10 mg/mL prior to UVB exposure | suppressed COX-2 and PGE2 expression; activation of PPAR-γ | [319] |
Wogonin | NIH/3T3 mouse skin fibroblasts | TPA, IL-1β and TNF-α and 10–100 mM wogonin for up to 2 h | decreased COX-2 and iNOS expression | [345] |
HaCaT | 0.1–10 mM for 72 h after UVB exposure | inhibited MMP-1 and IL-6; blocked MAPK/AP-1 and NF-κB pathways | [346] | |
Baicalin | human skin samples | 6.25–25 mg/mL after UVB exposure | decreased number of SA-β-Gal-positive cells; reduced G0/G1-phase cells; decreased expression of p16INK4A, p21CIP/Waf1 and p53; decrease in γ-H2AX levels; decreased expression of MMP-1 and MMP-3 | [320] |
Delphinidin | HaCaT | 5 or 10 µM before or after UVB exposure | restored elastic properties | [321] |
Extracts from yerba mate | HaCaT, BJ fibroblasts | 100–1000 µg/mL extracts | enhanced viability; inhibited activity of lipoxygenase, collagenase and elastase enzymes | [322] |
Extracts from leaves of Cleistocalyx nervosum var. paniala | human skin fibroblasts mushroom tyrosinase | 0.1 mg/ml | inhibition of MMP-2, ROS scavenging, lipid peroxidation inhibition, tyrosinase inhibition effect | [324] |
Mangiferin | human dermal fibroblasts | 10 μM/50 μM; 2 h followed by addition of H2O2 (10 μM) | decreased ROS production, stabilized mitochondrial membrane potential and decreased the number of cell cycle arrested cells | [323] |
Extracts from three species of seaweeds Alariaceae, Eisenia bicyclis, Ecklonia cava and Ecklonia stolonifera; eckol, dieckol, eckstolonol, triphlorethol-A and phloroglucinol | human dermal fibroblasts; HeLa cells transfected with the NF-κB or AP-1 luciferase reporter plasmid DNA; mushroom tyrosinase; B16F10 mouse melanoma cells; Zebrafish embryos; male 7-week-old Balb/c mice | 10 μg/mL extracts before treatment with TNF-α (10 ng/mL); exposure to UVB (50 mJ/cm2) + phlorotannins (0.5–250 μM); zebrafish embryos preincubated with 50 μM phlorotannins for 1 h; phloroglucinol (10 or 50 mg/mL) applied to dorsal skin plus UVB (30 or 60 mJ/cm2) | inhibited MMP-1; blocked AP-1 and NF-κB reporter activities; inhibition of tyrosinase, melanogenesis and DNA damage; reduction in ROS, NO, biomarkers of oxidative damage, cell death and hyperpigmentation in vivo; reduction in number of mast cells and increase in the epidermal and dermal thickness | [328,329,330] |
Phloroglucinnol | human WI-38 fibroblasts | 10, 25, 50, or 100 μg/mL phloroglucinol for 24 h after tratment with 50 μM H2O2 for 60 min | decrease in MDA in prematurely senescent cells and viability increase | [331] |
Polyphenol-rich extract from the seaweed Sargassum vachellianum | free radical scavenging, anti-tyrosinase activity and moisture absorption and retention assay | 200–1000 μg/mL | potential in scavenging OH radical, and effective absorption of the UVB and UVA rays | [333] |
Polyphenol-rich root extracts from Potentilla atrosanguinea | determination of total phenol content; free radical scavenging activity | dried aqueous-methanolic (H2O/MeOH) crude extract and ethyl acetate (EtOAc), n-butanol (n-BuOH), as well as aqueous (H2O) fractions of roots were evaluated (200 μg/mL) | H2O/MeOH crude extract showed highest antioxidant of DPPH radical scavenging, O2.− scavenging and Cu2+ reducing activity; photoprotective agents in sunscreen preparation; effective natural antioxidant | [325] |
Extract from tomato stem cell (Lycopersicon esculentum) | murin fibroblasts NIH-3T3; HaCaT | different concentration of the extract for 12 h or 2 h and/or CuSO4 for 30 min | reduced heavy metal-induced toxicity, restored DNA integrity under heavy metal stress; decreased collagen degradation and renewed collagen synthesis | [326] |
Verbascoside | HaCaT | 100 or 200 μmol/L added 2 min before UVC irradiation (20 min, 1.8 J/cm2) | decreased AP-1 and NF-κB and decreased level of proinflammatory mediators | [327] |
Extract from the parasitic mushroom Inonotus obliquus | skin fibroblasts, keratinocytes or reconstructed epidermis | 2% aqueous extract added 2 h before UV irradiation (UV-A (5 J/cm2) + UV-B (100 mJ/cm2) | reduced ROS formation, reduced quantity of pro-inflammatory cytokines and increased DNA repair activity | [334] |
Extract of the mycelium of Tricholoma matsuke | human skin fibroblasts | 0.1–100 μg/mL for 72 h and 24 h treatment in μcombination with TPA | decreased elastase activity, reduced the MMPs level | [336] |
Quercetin surface functionalized Fe3O4 nanoparticles | senescent human foreskin fibroblasts BJ; senescence induced by 100 μM H2O2 for 2 h | treatment with 5 μg/mL for 24 h | decreased number of stress-induced senescent cells; promoted AMPK activity; reduced IL-8 and IFN-β | [340] |
Quercetin/dasatinib | senescent MEFs from Ercc1−/− mice | 48 h treatment dasatinib (250 nM), quercetin (50 μM) | Reduction in senescent and total cell counts | [144,146] |
Fisetin | senescent MEFs from Ercc1−/− mice, IMR-90 fibroblasts | 48 h treatment, 1–15 μM | Reduction in the fraction of SA-ß-Gal-positive cells | [341] |
Curcumin luteolin | senescent MEFs from Ercc1−/− mice | 48 h treatment, 5 μM | Reduction in the fraction of SA-ß-Gal-positive cells | [341] |
Curcumin analog EF24 | senescent WI-38 and IMR-90 fibroblasts; senescence induced by replication, oncogene and IR | 72 h treatment | Selective killing of senescent cells; EC50 = 0.33–1.74 μM; proteasomal degradation of the Bcl-2 anti-apoptotic protein family proteins; independent of ROS | [342] |
Rhododendron ferrugineum leaves extract | senescent NHDF; senescence induced by 500 µM H2O2 for 2 h | 48 h treatment, 1% extract | Reduction in SA-ß-Gal-positive cells | [344] |
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Csekes, E.; Račková, L. Skin Aging, Cellular Senescence and Natural Polyphenols. Int. J. Mol. Sci. 2021, 22, 12641. https://doi.org/10.3390/ijms222312641
Csekes E, Račková L. Skin Aging, Cellular Senescence and Natural Polyphenols. International Journal of Molecular Sciences. 2021; 22(23):12641. https://doi.org/10.3390/ijms222312641
Chicago/Turabian StyleCsekes, Erika, and Lucia Račková. 2021. "Skin Aging, Cellular Senescence and Natural Polyphenols" International Journal of Molecular Sciences 22, no. 23: 12641. https://doi.org/10.3390/ijms222312641