Unlocking the Anti-Aging Potential of Apple (Malus domestica) Extract: In Vitro Modulation of TIMP-1, Casp-3, and GPX Gene Expression in Fibroblast Cells

Authors

  • Sri Utami Faculty of Medicine, Universitas YARSI, Central Jakarta, Indonesia
  • Qomaryah Romadhiyani Sachrowardi Faculty of Medicine, Universitas YARSI, Central Jakarta, Indonesia
  • Sonny Pamuji Laksono Faculty of Medicine, Universitas YARSI, Central Jakarta, Indonesia
  • Nunung Ainur Rahmah Faculty of Medicine, Universitas YARSI, Central Jakarta, Indonesia
  • Insan Sosiawan Tunru Faculty of Medicine, Universitas YARSI, Central Jakarta, Indonesia
  • Dewi Nurul Mustaqimah Faculty of Dentistry, Universitas YARSI, Central Jakarta, Indonesia
  • Eko Purwanto Faculty of Medicine, Universitas YARSI, Central Jakarta, Indonesia
  • Aryenti Faculty of Medicine, Universitas YARSI, Central Jakarta, Indonesia
  • Susi Endrini Faculty of Medicine, Universitas Abdurrab, Riau, Indonesia
  • Irfan Syarif Faculty of Medicine, Universitas YARSI, Central Jakarta, Indonesia
  • Kholis Ernawati Faculty of Medicine, Universitas YARSI, Central Jakarta, Indonesia
  • Wahyu Widowati Faculty of Medicine, Maranatha Christian University, Bandung, Indonesia
  • Dwi Nur Triharsiwi Biomolecular and Biomedical Research Center, Aretha Medika Utama, Bandung, Indonesia
  • Eksa Adhwa Fadhilah Biology Study Program, Faculty of Mathematics and Natural Sciences Education, Universitas Pendidikan Indonesia, Bandung, Indonesia
  • Dhanar Septyawan Hadiprasetyo Faculty of Pharmacy, Universitas Jenderal Achmad Yani, Cimahi, West Java, Indonesia
  • Haidir Syafrullah Nursing Study Program, Sekolah Tinggi Ilmu Kesehatan Dharma Husada Bandung, Bandung, Indonesia
  • Said Nafik Directorate General of Intellectual Property, Ministry of Law and Human Rights Republic of Indonesia, South Jakarta, Indonesia
  • Betharie Cendera Arrahmani Risk and Regulatory Consulting Pharma and Life Sciences, PricewaterhouseCoopers (PwC) GmbH WPG, Frankfurt, Germany

DOI:

https://doi.org/10.48048/tis.2025.10144

Keywords:

Anti-aging, Fibroblast cells, Oxidative stress, UV

Abstract

Ultraviolet (UV) exposure accelerates skin aging by inducing oxidative stress, apoptosis, and extracellular matrix degradation. Malus domestica (apple) extract (AE) is rich in antioxidants and bioactive compounds that may counteract these effects. This study evaluates the protective effects of AE on fibroblast cells exposed to UV radiation by assessing the expression of Tissue Inhibitor of Metalloproteinase 1 (TIMP-1), Caspase 3 (Casp-3), and Glutathione Peroxidase (GPX). Fibroblast cells were exposed to UV radiation and treated with different concentrations of AE (3.13, 6.25, 12.5 µg/mL). Gene expression levels of TIMP-1, Casp-3, and GPX were analyzed using qRT-PCR. AE significantly increased TIMP-1 and GPX expression while downregulating Casp-3 in a concentration-dependent manner. The highest concentration (12.5 µg/mL) demonstrated the most pronounced protective effects. These results suggest that apple extract enhances extracellular matrix stability, reduces oxidative stress, and inhibits apoptosis in UV-exposed fibroblasts. AE exhibits potent anti-aging properties by modulating key molecular pathways involved in skin damage. This study provides scientific evidence supporting its potential as an active ingredient in skincare formulations for UV protection and skin rejuvenation.

HIGHLIGHTS

  • Apple extract significantly upregulated TIMP-1 and GPX expression while downregulating Casp-3, indicating enhanced extracellular matrix stability and reduced apoptosis.
  • The findings suggest that apple extract mitigates oxidative stress and inhibits apoptosis, which are key contributors to skin aging.
  • A dose-dependent effect was observed, with the highest concentration (12.5 µg/mL) demonstrating the most significant anti-aging impact.

GRAPHICAL ABSTRACT

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References

C López-Otín, MA Blasco, L Partridge, M Serrano and G Kroemer. The hallmarks of aging. Cell 2013; 153(6), 1194-1217.

R Ganceviciene, AI Liakou, A Theodoridis, E Makrantonaki and CC Zouboulis. Skin anti-aging strategies. Dermato-Endocrinology 2012; 4(3), 308-319.

L Rittié and GJ Fisher. Natural and sun-induced aging of human skin. Cold Spring Harbor Perspectives in Medicine 2015; 5(1), a015370.

F Gruber, C Kremslehner, L Eckhart and E Tschachler. Cell aging and cellular senescence in skin aging - Recent advances in fibroblast and keratinocyte biology. Experimental Gerontology 2020; 130(9), 110780.

P Gkogkolou and M Böhm. Advanced glycation end products: Key players in skin aging? Dermato-Endocrinology 2012; 4(3), 259-270.

S Zhu, L Jia, X Wang, T Liu, W Qin, H Ma, Y Lv, J Hu, Q Guo, S Tan, X Yue, Y Yan, T Liu, Y Liu, Q Xia, P Zhang, H Zhang and N Li. Anti-aging formula protects skin from oxidative stress-induced senescence through the inhibition of CXCR2 expression. Journal of Ethnopharmacology 2024; 318(B), 116996.

LC Hunt, A Upadhyay, JA Jazayeri, EM Tudor and JD White. Caspase-3, myogenic transcription factors and cell cycle inhibitors are regulated by leukemia inhibitory factor to mediate inhibition of myogenic differentiation. Skeletal Muscle 2011; 1(1), 17.

M Xu, T Pirtskhalava, JN Farr, BM Weigand, AK Palmer, MM Weivoda, CL Inman, MB Ogrodnik, CM Hachfeld, DG Fraser, JL Onken, KO Johnson, GC Verzosa, LGP Langhi, M Weigl, N Giorgadze, NK LeBrasseur, JD Miller, D Jurk, RJ Singh, …, JL Kirkland. Senolytics improve physical function and increase lifespan in old age. Nature Medicine 2018; 24(8), 1246-1256.

R Brigelius-Flohé and M Maiorino. Glutathione peroxidases. Biochimica et Biophysica Acta 2013; 1830(5), 3289-3303.

L Calvo‐Castro, M Lobo-Vázquez, J Gómez-González, E Arnáez-Serrano, G Zamora-Fallas, K Sánchez-Zúñiga, and C Centeno-Cerdas. Bioactive potential of tropical highland apple (Malus domestica cv. Anna) crude extract: opportunities for food waste revalorization. Future Journal of Pharmaceutical Sciences. 2022; 8(1), 57.

N Nanashima, H Maeda, A Nakajima, M Nishizuka, T Narumi, J Ichita and K Itoku. Apple pomace extract induces cell proliferation and increases type I collagen and hyaluronan production in human skin fibroblasts in vitro. Plant Foods for Human Nutrition 2024; 79(3), 693-699.

L Orozco-Flores, E Salas, B Rocha‐Gutiérrez, M Peralta-Pérez, G González-Sánchez and L Ballinas‐Casarrubias. Determination of polyphenolic profile of apple pomace (Malus domestica Golden Delicious variety) by HPLC-MS. ACS Omega 2023; 9(1), 196-203.

S Balık, T Kaya and R Aslantaş. Fruit quality parameters, sugars, vitamin C, antioxidant activity, organic acids, and phenolic compounds for a new endemic apple variety “Long Apple”. Horticulturae 2023; 9(11), 1171.

K Bindon, Q Song, S Kassara, L Nicolotti, A Jouin and M Beer. Apple pomace compositional data highlighting the proportional contribution of polymeric procyanidins. Molecules 2023; 28(14), 5494.

D Khayatan, M Nilforoushzadeh, H Ashtiani and F Hashemian. Effect of apple (Malus domestica) stem cells on UVB-induced damaged skin with anti-inflammatory properties: An in vivo study. Advances in Materials Science and Engineering 2022; 2022(5), 1-13.

HJ Kim, SH Kim and JM Yun. Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. Evidence-Based Complementary and Alternative Medicine 2012; 2012(3), 639469.

DG Lazaridis, AP Kitsios, AS Koutoulis, O Malisova and IK Karabagias. Fruits, spices and honey phenolic compounds: a comprehensive review on their origin, methods of extraction and beneficial health properties. Antioxidants 2024; 13(11), 1335.

W Widowati, D Pryandoko, CD Wahyuni, M Marthania, HS Kusuma and T Handayani. Antioxidant properties of soybean (Glycine max L.) extract and isoflavone. In: Proceedings of the 2021 IEEE International Conference on Health, Instrumentation & Measurement, and Natural Sciences (InHeNce), Medan, Indonesia. 2021, p. 1-6.

W Widowati, DK Jasaputra, P Onggowidjaja, SB Sumitro, MA Widodo, E Afifah, DD Rihibiha, R Rizal, A Amalia, HSW Kusuma, H Murti and I Bachtiar. Effects of conditioned medium of co-culture IL-2 induced NK cells and human Wharton’s jelly mesenchymal stem cells (HWJMSCs) on apoptotic gene expression in a breast cancer cell line (MCF-7). Journal of Mathematical and Fundamental Sciences 2019; 51(3), 205-224.

E Afifah, T Mozef, F Sandra, S Arumwardana, DD Rihibiha, H Nufus, R Rizal, A Amalia, I Bachtiar, H Murti and W Widowati. Induction of matrix metalloproteinases in chondrocytes by interleukin IL-1β as an osteoarthritis model. Journal of Mathematical and Fundamental Sciences 2019; 51(2), 103-111.

AV Anand David, R Arulmoli and S Parasuraman. Overviews of biological importance of quercetin: A bioactive flavonoid. Pharmacognosy Reviews 2016; 10(20), 84-89.

G Bjørklund, M Shanaida, R Lysiuk, M Butnariu, M Peana, I Sarac, O Strus, K Smetanina and S Chirumbolo. Natural compounds and products from an anti-aging perspective. Molecules 2022; 27(20), 7084.

A Francini and L Sebastiani. Phenolic compounds in apple (Malus × domestica Borkh.): compounds characterization and stability during postharvest and after processing. Antioxidants 2013; 2(3), 181-193.

T Huang, Q Che, X Chen, D Chen, B Yu, J He, H Chen, J He, P Zheng, Y Luo and B Yu. Apple polyphenols improve intestinal antioxidant capacity and barrier function by activating the NRF2/KEAP1 signaling pathway in a pig model. Journal of Agricultural and Food Chemistry 2022; 70(24), 7576-7585.

Q Ma, J Gao, P Fan, T Yang, Z Zhuang, S Zhang, R Hu, L Cui, B Liang, X Xie, J Liu and J Long. Thinned young apple polyphenols may prevent neuronal apoptosis by up-regulating 5-hydroxymethylcytosine in the cerebral cortex of high-fat diet-induced diabetic mice. Food & Function 2023; 14(7), 3279-3289.

C Joshi, S Stacy, N Sumien, A Ghorpade and K Borgmann. Astrocyte HIV-1 Tat differentially modulates behavior and brain MMP/TIMP balance during short and prolonged induction in transgenic mice. Frontiers in Neurology 2020; 11, 593188.

L Xiao, T Zhu, S Yang, X Li, B Song, Y Wang, Q Lin and J Cao. Analysis of phenolic components and related biological activities of 35 apple (Malus pumila Mill.) cultivars. Molecules 2020; 25(18), 4153.

W Xia, B Song, T Li and RH Liu. Phytochemical profiles, antioxidant activities, and synergistic antiproliferative effects of blueberry and apple peel extracts. Journal of the Science of Food and Agriculture 2023; 104(2), 737-745.

AS Ribeiro, M Estanqueiro, MB Oliveira and JMS Lobo. Main benefits and applicability of plant extracts in skin care products. Cosmetics 2015; 2(2), 48-65.

Z Wu, Q Xu, A Li, L Lv, L Li. Apple polyphenol extract suppresses Clostridioides difficile infection in a mouse model. Metabolites 2022; 12(11), 1042.

D Li, Y Cui, X Wang, F Liu and X Li. Apple polyphenol extract improves high-fat diet-induced hepatic steatosis by regulating bile acid synthesis and gut microbiota in C57BL/6 male mice. Journal of Agricultural and Food Chemistry 2021; 69(24), 6829-6841.

J Wei, Q Xie, X Liu, C Wan, W Wu, K Fang, Y Yao, P Cheng, D Deng and Z Liu. Identification of the prognostic value of glutathione peroxidases expression levels in acute myeloid leukemia. Annals of Translational Medicine 2020; 8(11), 678.

M Nazıroğlu. A novel antagonist of TRPM2 and TRPV4 channels: Carvacrol. Metabolic Brain Disease 2022; 37(3), 711-728.

S Wen, Q Wang, J Jia, X Gong, Y Zhao and G Li. Downregulation of IGFBP7 and TIMP-2 protects kidney cells by regulating cell cycle in sepsis-associated acute kidney injury, Available at: https://doi.org/10.21203/rs.3.rs-2975261/v1, accessed January 2025.

X Yao, Y Mei and W Mao. Quercetin improves mitochondrial function and inflammation in H₂O₂-induced oxidative stress damage in the gastric mucosal epithelial cell by regulating the PI3K/AKT signaling pathway. Evidence-Based Complementary and Alternative Medicine 2021; 2021, 1386078.

KT Mellody, E Bradley, B Mambwe, L Cotterell, O Kiss, P Halai, Z Loftus, M Bell, TW Griffiths, CEM Griffiths and REB Watson. Multifaceted amelioration of cutaneous photoageing by (0.3 %) retinol. International Journal of Cosmetic Science 2022; 44(6), 625-635.

S Omar, RM El Borolossy, TW El-Said and NA Sabri. Evaluation of the combination effect of rutin and vitamin C supplementation on the oxidative stress and inflammation in hemodialysis patients. Frontiers in Pharmacology 2022; 13, 961590.

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Published

2025-08-01

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