Table 1.

Polyphenols with anti-senescence potential investigated in skin cells in vitro.

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]

AP-1, activator protein 1; COX-2, cyclooxygenase 2; DPPH, 2,2-diphenyl-1-picryl-hydrazyl-hydrate; ER, endoplasmic reticulum; ERK, extracellular-signal-regulated kinase; HaCaT, human immortalized keratinocytes; HO-1, heme-oxygenase 1; IFN-β, interferon beta; IL-1, -6, -8, interleukin 1, 6, 8; iNOS, inducible nitric oxide synthetase; IR, ionization radiation; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MDA, malondialdehyde; MEFs, mouse embryonic fibroblasts; MMP-1, matrix metalloproteinase 1; NHDF, normal human dermal fibroblasts; NHEK, normal human epidermal keratinocytes; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NO, nitric oxide; Nrf2, nuclear factor erythroid 2–related factor 2; PGE2, prostaglandin 2 PI3K, phosphatidylinositol 3-kinase; PPAR-γ, peroxisome proliferator-activated receptor gamma; ROS, reactive oxygen species; SA-β-Gal, senescence associated b-galactosidase.